6-fluoromethyl steroid compounds and process



Patented Jami v 3,189,604 7 fi-FLUOROMETHYL STEROID COMPOUNDS AND PROCESS Philip F. Bea! III and John E. Pike, Kalamazoo, Mich., assignors to The Upjohn Company, Kalamazoo, Mich., a corporation of Delaware No Drawing. Filed June 16, 1960, Ser. No. 36,471

19 Claims. (Cl. 260-43955) This application is a continuation-in-part of our Y-- pending application Serial No. 1,421 filed'lanuary 11, 1960, now abandoned. I 00 This invention relates to certain novel steroids, more particularly to Ga-fluoromethyl-llfi,17,2l-trihydroxy-4- pregnene-3,20-dione, 6a-fluoromethyl-l7a,2l-dihydroxy- 4-pregnene-3 1 1 ,ZO-trione, 6a-fluoromethyl-l 1,8, l7'a,21-trihydroxy-lA-pregnadiene 3,20 dione, fia-fluoromethyh 17a,2l-dihydroxy-l,4-pregnadiene 3,11,20 trione. 6-fiuoromethyl 1lfi,l7a,2l trihydroXy-4,6-pregnadiene-3,20- dione, 6-fiuoromethyl-l7u,2l-dihydroxyl,6-pregnadiene- 20 3,11,20-trione, 6 fiuoromethyl 11B,17a,21 tr-ihydroxyl,4,6-pregnatriene-3,ZO-dione, 6-fluoromethyl-l7a,2l-dihydroxy-l,4,6-pregnatr-iene-3,l1,20-trione, the 9a-halo, especially the 9u-fluoro, compounds corresponding otherwise thereto, 21-esters of each, the corresponding ZI-fluoro 25 and 2l-desoiry compounds including the 17-acylates there- Y of, and intermediates in the production thereof. It further relates to the 2a-alkyl, lfiu-alkyl, 16/3-alkyl, 16w 0: hydroxy and l6a-acyloxy derivatives of these compounds, and in those compounds wherein the lfi-substituen't is a-hydroxy, to the 16u,l7a-acetonides thereof.

The novel compounds of this invention and a process for their production can be illustrated by the following formulae:

O-CH;

CHgOAc froni XXI, XXIII,

"XXV, XXVILaHd XXVIII CHzOSOzR (I: 7

CHQF

Y" I Y r V (XXXI) (XXIX) cum omr respiratory tract and the bones and internal organs due wherein Ac is the acyl radical of a hydrocarbon ca-rboxylic acid containing from 1 to 12 carbon atoms, inclusive; R. is an organic (alkyl or aryl) radical containing up to and including carbon atoms; R and R" are selected from the group consisting of hydrogen, a loWer-alkyl,

radical, a monocyclic aromatic radical, a monocyclic aromatic lower-alkyl radical, a monocyclic heterocyclic radical, and a monocyclic heterocyclic lower-alkyl radical;

R and R. when taken together are alkylene; W is selected from the group consisting of the carbonyl radical C=O) and the B-hydroXy-methylene radical X is selected from the group consisting of hydrogen, hydroxy, acyloxy and fluorine; Y is selected from the group consisting of hydrogen and methyl; Y in Formulae I to XII is selected from the group consistingof hydrogen, a-methyl, and B-methyl; Y in Formulae )GI to XXXI is selected from the group consisting of hydrogen, tit-methyl, fi-methyl, and ec-hYdlOX Z is a halogen having an atomic weight from to 127, inclusive, i.e., chlorine, bromide or iodine; Z is a halogen having an atomic weight from 19 to 127, inclusive, i.e., fluorine, chlorine, bromine, or iodine; Z is hydrogen, fluorine or chlorine. The broken lines appearing inside the rings in Formulae XIV to XXXI indicate A and A -double bonds which may or may not be present and represent A ,A ,A and A -compounds.

As used in this application, the Roman numeral following the name of a compound (or compounds) indicates the relation of the compound (or compounds) to the reaction scheme depicted above.

The novel compounds of this invention, 6a-fluoromethyl-l1B,17,2l-trihydroxytapregnene,20 dione, 6a-fluoromethyl 170:,21 dihydroxy-4-pregnene-3,11,20- trione, a-fiuoromethyl 11,8,17a,21 trihydroxy-lA-pregnadiene-3,20-dione, om-fluoromethyl 1711,21 dihydroxy- 1,4pregnadiene-3,11,20-trione, 6 fiuorornethyl 7 11,3,17u, 21 trihydroxy 4,6 pregnadiene 3,20 dione, 6 iiuorome-thyl-17u,2l-dihydroxy 4,6 pregnadiene-3,11,20-

trione, 6 -fluoromethyl 11B,17a ,21 trihydroiry 1,4,6

pregnatriene-3,20-dione, 6 fluo-romethyl 170:,21 dihydroxy-l,4,6-pregnatriene-3,11,20-trione, the 90: halo, especially the 9a-fluoro, compounds corresponding otherwise thereto, ZI-esters of each, the corresponding 21- fiuoro-and 21-desoxy compounds, including the 17- acylates thereof, the Za-alkyl, loa-alkyl, 16B-all;yl, 16ahydroxy and la-acyloxy derivatives of these compounds and in those compounds wherein the 16-substituent is a-hydroxy, the 16a, 17a-acetonides thereof, are highly potent cortical hormones having anti-infiammatory, salt and Water regulating, pituitary inhibiting, progestational and anti-anabolic activities with improved ratio of therapeutic activity to undesirable side-eifects, e.g., gastrointestinal disturbances, edema, etc., known to exist with similar known physiologically active steroid compounds.

Many of the higher molecular Weight esters, particularly;

those resistant to hydrolysis and/or more insoluble inbody fluids, provide compounds having more prolonged activity than the corresponding 21-hydroxy compounds.

The above-named compounds are useful in the treatment of various inflammatory conditions of the skin, eyes,

to bacterial ,or viral infections, contact dermatitis and allergic reactions, rheumatoid artbritis, and possess improved therapeutic ratios of anti-inflammatory activity to undesirable side-effects, compared to the corresponding.

compounds lacking the Ga-fIuO-romethyl group. For this purpose the compounds of this invention may be incor porated and administered to mammals, birds and animals, in the various ointments, creams, lotions, sprays, tablets,

suspensions and solutions for systemic and/ or topical application well known in the art. They may be combined with the known antibiotics, especially the "penicillinsj neomycin, tetracycline, chloromycetin, and novobiocin and with anti-fungal agents, such. as griseofulvin.

Other compounds of this invention, as--well as being useful as intermediates in the production of'the above 6:4 fiuoromethyl hydroxy I7a,2 1 epoxy 4- pregnene 3,20 dione, 60c fluoromethyl 11 3 hydrOXy- :,21 epoxy 9a fluoro 1,4 pregnadiene 3,20 dione and 6 fluoromethyl 11B,16ordihydroxy 17a,

2-1 epoxy 9a fiuoro 1,4,6 pregnatriene 3,20 dioneare formed as by-products during the synthesis of the closely related 21-fluoro-17a-hydr0Xy compounds ern-- braced by Formula XXIII, e.g., 6a-fluoromethyl-11fi,17a-' dihydroxy 21 fiuoro 4 -pregnene 3,20 dione, 6ozfiuoromethyl --11,8,17wdihydroxy 9a,21 difluoro 1,4- pregnadiene 3,20 dione and 6 fiuoromethyl- 11 8,16a, 17cc trihydroxy 9m,21 difiuoro 1,4,6 pregriatriene- 3,20-dione. The 170:,21-6POXY compounds of Formula XXIV possess marked diuretic activity.

The novel compounds of the present invention are prepared from the known cortisone (or the Zea-methyl, 16ccmethyl, and 16,8-methyl derivatives thereof) (1) by the following reactions: The 17a,21-dihydroXy-20-keto steroids (I) are converted by treatment with formaldehyde in the presence ofa strong acid (hydrochloric, perchlo ric, sulfuric and the like acids) to the corresponding 17:20, 20:21 bismethylenedioxy 4 -pregnene 3,11- dione (II).

The next step of the process of this invention involvesenol acylation of 17:20, 20:21-bismethylenedioXy-4-pregnene-3,11-dione (II) with an alkenyl acylate in the presence of an acid catalyst, e.g., isopropenyl acetate in the presence of p-toluenesulfonic acid, or other enol acylating agent, to produce a 17:20, 20:21-bismethylenedi0xy- 3,5-pregnadien-11-one 3-acylate (III). Reacting the thus produced 17 20, 20 2l-bismethylenedioxy-3,S-pregnadienll-one 3-acylate (III) with sodium borohydride or other appropriate reducing agent followed by reacylation yields a 17:20, 20:2l-bismethylenedioxy-5-pregnene-3p,1lfi-dihydroxy 3-acylate (IV).

The next step of this invention comprises hydroxymethylating the thus obtained 17:20, 20:21-bismethylenedioXy-5-pregnene-3 3,1=1B-diol 3-acylate (IV) at the 6-po- V sition by reacting the compound" under conventional 0X0 reaction conditions with carbon monoxide and hydrogen under superatmosperic pressure to produce 17:20, 20:21 bismethylenedioxy 60c hydroxymethyl 5w pregnane-3fl,11B-diol 3-acylate (V).

' The next step of the process of this invention involves the reaction of the thus produced 17:20, 20:21-bismeth Q droxy 9o: fiuoro 4,6-pr egnadiene-3,11,20-trione and 6 fiuoromethyl-l701,21-dihydroxy-9u fluoro-l,4,6pregnatriene-3,11,20-trione and the remaining compounds represented collectively by XX. I The esters of XIX are similarly hydrolyzed to the corresponding 21-hydroxy compounds.

The Ga-fiUOX'OIHEthYl-Zl-fillOl'O compounds of this invention are prepared by treating 6ct-flucn-omethyl-ll,8,1'7az,2l-. trihydroxy-4-pregnene-3,ZO-dione and the additional compounds represented by Formula XXI or the corresponding l l-keto compounds, with an organic sulfonyl halide such as methanesulfonyl chloride, toluenesulfonyl bromide, benzenesulfonyl chloride, naphtha-lenesulfonyl chloride, or the like, in the manner disclosed in U.S.v Patent 2,83 8,543 to obtain the corresponding 2 l-sulfonate ester (XXII), e. g., 6a-fluoromethyl-l118,1701,21-trihydroxy-4-pregnene-3, 20-dione 21-methanesulfonate or 2lp-toluenesulfonate; treating the thus-produced 21-a1kyl tor aryl'sulfonates with sodium iodide in acetone solution to obtain the corresponding 21-iodo compounds (XXVI), e.g., a-fluoromethyl 115,17a di-hydroxy 21-iodo-4-pregnene-3,20-dione and 6afluoromethyl-115,17adihydroXy-2l-iodo 9afiu-oro-l,4-pregnadiene-3,20-d-ione; treating the thus obtained 2l-iodo compounds with silver fluoride, preferably in acetonitrile solution, to obtain the corresponding 21- fluoro compounds embraced by Formula XXIII, e.g., 6cfiuoro l1fi,l7cz dihydroxy-Zl fluoro-4-pregnene-3,20-dione, 60: fluoromethyl-l15,17u-dihydroXy-9a,21-difluoro- 1,4-pregnadiene-3,i20-dione and 6-fluoromethyl-2-methyll 1,8,17u-dihydroxy-9 a-chloro-Zl-fiuoro-l ,4,6-pregnatriene- 3,2G-dione; and if desired, oxidizing the thus obtained 21- fluoro compounds with chromic anhydride, N-bromo- V acetamide, 'N bromosuccinimide, or the like, to give the corresponding ll-keto compounds (XXV), e.g., 6a-fluoromethyl l7u-hydroxy 21-fluoro-4-pregnene-3,11,20-trione, 60c fluoromethyl 17a hydroxy-9mll-difluoroAlA-pregnadiene3,11,20-trione and 6-fluoromethyl-2-methyl-l7ahydroxy 9m chloro 21-fluoro-1,4,6-pregnatriene-3,11, 20-.trione. Alternatively, the ZI-sulfonates (XXII) preferably the 2l-methanesulfonates, can be treated directly with potassium fluoride in dimethyl sulfoxide, e.g., at 100 C. for a period of -18 hours or longer, to produce directly the 6a-fiuoromethyl-2l-fiuoro compounds (XXIII) in addition to minor amounts of the 6a-flu0romethyl-17a,2l-epoxy compounds (XXIV), e.g., -6afluoromethyl-11,8,17a-dihydroxy-Z1-fluoro-4-pregnene-3,ZO-dione (XXIII) plus 60:- fiuoromethyl 11,8 hydroxy 17 0:,21 epoxy-4-pregnene- 3,20-d-ione (XXIV). The corresponding ll-keto analogues of the compounds embodied in Formula XXIII, are prepared by oxidizing the 1 lfi-hydroxy group of compounds represented by Formula XXIII.

The 21-unsubstituted compounds of this invention (XXVII and XXVIII) are prepared by treating a 2l-iodo compound included in Formula XXVI, e.g., 6a-fluoromethyl-1lfi,17a-dihydroxy-2l-iodo-4-pregnene-3,2O dione and -fiuoromethyl-l6 li-methyl-1IfiJH-dihydroxy 9afiuoro-21-iodo-:1,4,6-pregnatriene3,ZO-dione, with a reducing agent such as sodium thiosulfate, sodium bisulfite, potassium thiosulfate, or the like, in an aqueous-organic solvent mixture, to obtain the corresponding 21-unsubstituted compound (XXVII) and if desired oxidizing the thus obtained Zl-unSubstituted compound with chromic anhydride, N-brcmoacetamide, N-bromosuccinimide or the like, to give the corresponding 11 keto' compound (XXVIII), e.g., 6a-fluoromethyl-17e-l1ydroxy-4-pregnene- 3,11,20-trione and fi-fiuorornethyl-l6p1methyl-l7a hydroXy-9cc-fluoro-1,4,6-pregnatriene-3,1 1,20-trione.

The 17-acylates (XPGX and XXXI) of the 'Zd-u'nsub stituted compounds (XXVII and 'XXVIII) of this invention are prepared by esterifying the corresponding 17- hydroxy steroids, e.g., with the anhydride of the selected acid or with formic acid, in the manner for esterifying difiicultly esterifiable hydroxy steroids disclosed in US.

Patent 2,805,230. This esterification can readily be ac complished by reacting the starting steroidwith the select- 19 ed anhydride in the presence or" an acid catalyst, e.g., ptoluenesulfonic acid. Following this procedure, 6a-fiuodione (XXVII) and 6-fiuoromethyl-2a-rnethyl-17a hydroxy-4,6-pregna-diene-3,11,20 trione (XXVIII) heated with acetic anhydride, p-toluenesulfonic acid and acetic acid yield the corresponding 6a-fluoromethyl-1lB,17adihydIoXy-Qa-fluoro-4-pregnene-3,20 dione 17 acetate (XXIX) and d-tluoromethyl-h-methyl-l7a-hydroxy 4,6

pregnadiene-3,l1,26-trione 17-acetate (XXXI).

The 1604,17cc-3C6l21l derivatives of the compounds of this invention ()C(X) are prepared from the steroids represented by Formulae XII, XIV, XIX, XX, XXI XXIII,

XXV, XXVII and XXVIII, wherein Y is a u-hydroxy, (prepared as in Example 7613) by treating a suspension or solution of the selected steroid in an aldehyde or ketone (either alone or in a suitable solvent When the aldehyde or ketone is a solid) with an acid catalyst such as perchloric acid, p-toluenesulfonic acid, hydrochloric acid or the like, neutralizing the acid and recovering the acetal derivative thus produced. For example, acetone solutions of 6ix-fluoromethyl-11,8,16a,l7cz,2l-tetrahydroxy-4 pregnene-3,20-dione (XII) and 6a-fiUOIOHIEthYl-llfl',16a, l7u, 21-tetrahydroxy-9a-fiuoro-1,4 pregnadiene 3,20 dione (XXI) when reacted with perchloric acid yield 6u-fluoromethyl-l113,16ul7a,2l-tetrahydroxy 4 pregnene 3,20- dione l6u,l7a-acetonide (XXX) and 6ix-fiuoromethyl- 1'13,16a,17u,21-tetrahydroXy-9a-fiuoro-1,4 pregnadiene- 3,20-dione l6tx,l7a-acetonide (XXX).

The compounds of this invention represented by Formula IX can be prepared by an alternative process not requiring the formation of 17:20,20z21-bismethylenedioxy derivatives. The compounds represented by Formula IX can be prepared as follows: oxidizing 3B,11,6,l7a,2l-I6i121- hydroxy-Spregnen-ZO-one 3,2l-diacetate (1) (prepared according to US; Patent 2,899,448) with chronic acid to produce the corresponding ll-keto compound (2); hydrolyzing the thus-produced 3B,'17a,2l-trihydroxy-S-pregnene-1l,20-dione 3,21-diacetate (2) with potassium hydroxide or potassium carbonate in aqueous methanol at room temperature for a period of about 24 hours to yield 3,8,17u,21-trihydroXy-5-pregnene-11,20-dione (3); refluxing the thus produced 3B,17,2l-trihydroxy-S-pregnene- 11,20-dione (3) for about 6 hours under a water takeofi head with ethylene glycol in benzene containing p-toluenesulfonic acid to give the corresponding ZO-ethylene ketal (4); dissolving the thus-obtained 3fi,17a,21-trihydroXy-5- pregnene liiO-dione ZO-ethylene ketal (4) in acetic anhydride and pyridine overnight at room temperature to yield 35,17a,2l-trihydroxy-S-pregnene-l1,20-dione ZO-ethylene ketal 3,21-diacetate (S); hydroxyrnethylating the thus obtained 3fi,17ot,21-trihydroXy-5 pregnene 11,20- dione ZO-ethylene ketal 3,2l-diacetate (5) at the 6-position of the non-conjugated double bond by reacting said compound with carbon monoxide and hydrogen in the presence of an operative catalyst, e.g., cobalt carbonate, under superatmospheric pressure to produce oa-hydroxymethyl- 3 8,l7a,2l-trihydroXy-Su-pregnane-1 1,ZO-dione 2O ethylene ketal 3,2l-diacetate (6); reacting the thus-produced 6a-hydroxyrnethyl-3fi,17c,2I-trihydIoXy-Su-pregnane 11, ZO-dione ZO-ethylene ketal 3,21-diacetate (6) with an organic sulfonyl halide, e.g., p-toluenesulfonyl chloride, to obtain the corresponding 6-tosyloxymethyl derivative (7); reacting said 6-tosyloxymethyl compound (7) with an alkali metal fluoride, e.g., potassium fluoride, to give 60:- fiuoromethyl-3B,17a,2I-trihydrQXy-Sa pregnane 11,20- dione ZO-etnylene ketal 3,21-diacetate (8); reducing the thus-produced 6a-fluoromethyl-3fi,17a,21-trihydro ry 5ozpregnane-ll,20-dione ZO-ethylene ketal 3,2l-diacetate (8) with lithium aluminum hydride to yield 6afluoromethyl- 3,8,115,l7a,21-tetrahydroxy-Saregnan-ZO-One 2U ethylene ketal (9); dissolving the thus obtained 6tx-fluoromethyl-3,8,1 1 8,17a,2l-tetrahydroxy-Saregnan-ZO-one 2O ethylene ketal (9) in acetic anhydride and pyridine with standing overnight at room temperature to. reesteriiy and 3,20-dione ZI-acetate (IX).

' tuting 'tuting V g V V trione (i). (J. Amer. Chem. Soc. 80, 3160 [1958]) as the starting steroid, there is thus produced 17:20,20:21-bisrestore the acetate groups atthe 3 and 21-positions; par

tially hydrolyzing the thus-obtained 6a fiuoromethyl- 33,11B,17a,21-tetrahydroXy-oi-pregnan-20-one 20 ethyl-.

ene ketal 3,21-diacetate (9) with potassium-bicarbonate in aqueous methanol to give 6 t-fluoromethyl-3p2,110,1701,v

21-tetrahydro y-5a-pregnan-20one ZO-ethylene ketal 21- acetate (.10); oxidizing (Oppenauer) the thus produced 6a-fluoromethyl-3 3,1 15, l 70:,2 I-tetrahydrOXy-Su' pregnan- 20-one 20-ethyleue ketal 21-acetate (10) with a; ketone, e.g., acetone, and an aluminum alkoxide, e.g.,- aluminum' 'isopropoxide, to yield the corresponding a-fiuorome hy 11,3,17a,2l-trihydroxy-5 -pregnan-3-one ZO-ethylene ketal 21-acetate 1(11); removing the ZO-ethyIene'ketal group from the thus produced oc-fiuoromethyl-l1p,17 x,21-tri1 hydrOXy-Saregnan-B-one ethylene 'ketal 21 acetate ('11) by heatingsaidcompound in aqueous acetone with dilute sulfuric a'cid on a steam bath to give out-fluoromethyl-l1 8,17a,21-trihydroXy-5a-pregnarr-3,20 dione 21-.

acetate (12) and dehydrogenating the thus-obtained 6afluoromethyl-l118,17,21-LihydroXy-5a pregnan 3,20-

' dione '21-acetate ('12) in the 1,2-and 4,5-positions by means of selenium dioxide to obtain 6a-fluoromethyl-llfi, 17a,21-trihydroxy-1,4-pregnadiene-3,20 dione 21 acetate Following the procedure outlined above for the'preparation 'of V 6ok-fluoromethyl-11fi,17a,2l-trihydroXy-1,4

pregnadiene-ZvJO-dione ZI-acetate (IX), but instead of 313,11,8,1701,21-tetrahydroxy-5-pregnen-2O-one 3,21-diacetate (1), substituting a corresponding Zoe-methyl, 161xmethyl or Ids-methyl derivative thereof as starting compound, there is thus produced the corresponding 20:-

methyl, 16a-methy1 or 16,8-methyl substituent of 6a- The following preparations and examples are illustrative of the process and products of this invention.

PREPARATION 1 1720,2.0:21-17ismethyleizedi0xy-4-pregizene-3Jl-diolze A mixture of 200 g of 4 pregnene-17a, 21-dihydroxy- 3,11,20-trione (cortisone) (I), 4000 ml. of chloroform, 2500 ml. of 38% aqueous formaldehyde and 2000 ml. of concentrated hydrochloric acid was stirred at room temperature for a period of about 20 hours. The chloroform layer was separated, washed twice with water, sodium bicarbonate solution and again with water. chloroform extract was dried with sodium sulfate, the solvent evaporated and the residue crystallized from methanol to give 136 g. of light colored crystalline solid 17:20,20:21-bismethylenedioXy-4-pregnene 3,11 dione with a melting point of 244 to 24 C. and a rotation [111 of plus 82in chloroform. A second crop of 9 g. (after recrystallization) was obtained from the mother liquor PREPARATION 3.

. pregame-3,1 I-dz'ojrg'e (II) V Following'the procedure of Preparation lpbut substi- 16ci-methyl-17a,21-dihydroXy-4-pregnene-3,1 1,20-

methylenedioxyla-methyh -pregnenefi;1ldione (II).

The

' anhydride Was added to the filtrate and the reactionmix- V ture heated on a'steam bath for about 1.5'h0urs; After.

cooling, the solution was poured into 3000 ml. ofice" .water, allowed to stand at 0-5 'C., collected by filtration,

tuting PREPARATION 4 V 1 7:20,20:2]{tismethyleriedioxyJ6,8-methyi I Following the procedure of lPreparatiori l, but substii' 16fi-methyl-179,21-dihyd1'oXy-4-pregnene-3,1 1,20

trione (I) (J. Amer. Chem. Soc. 80', 4435" [1953]).as

the starting steroid, there is thus produced 17':20,20: 21 bismethylenedioxy-16fi-methyl-4 pregnene 3,11 dione .10 Y

i 'EXAMI I IZ 'I 17:20,20:2ZJiismethylenedioxy ipregnllee 31?,11-1611'01 3-acetate (IV i i 85.9 g. of 17120,20:21 bismethylenediokyi-pregnene- 3,11-di0ne (II),'750'ml. of isopropenyl acetate', 2.5 gfof} p-toluenesulfonic acid .monohydrate"and fl000 ml. .of

toluene were placed in a 3 liter flask fitted with a'stirrer',

heating mantle. and condenser. Theheating'ot'the mixture was regulated so that 200 of distillate was collected over a 2 hour period. An additional 500 m1. of

toluene and 750ml. of isopropenyl acetate was added and 1200 ml. of distillate collectedlovera t.hour-period. The reaction mixture was then concentrated to a'volume.

of about 200 ml. on a water bath held at a temperature 7 of to C. 1000 ml. more of toluene was added a nd the solution concentrated to a volume of about 200 ml. under vacuum. Benzene, was added to the residue-and the organic solution washed first'with 5 aqueous sodium bicarbonate solution then'water and dried with sodium sulfate; The benzene solution was stirred with 40 g. each' of Florisil and Magnesol (synthetic magnesium silicates) fora period of about l hour and then filtered. Evapora tion of the solvent and crystallization of the resulting residue gave 48.1 g. (51% yield) of l7:20,20:21-bismethylened-ioxy-3,5-pregnadien-1l-one.3 acetate '(III) with a melting point of 'l82 C. 70 g. of III, prepared in this manner, was dissolved in 1750 ml. of dioxaneand the resulting solution cooled to 0 to 5' C. To-this solu-.

tion, over a period of 30 minutes, 70 g. of sodium'borohydride dissolved in 7.00 ml. of 0.1 N sodium hydroxide Was added. After a period of about 50 hours at room 7 temperature the excess sodium borohydride wasrdecomposed bythe addition of 50% aqueous acetic acid. 900

ml. of water was added and after prolonged cooling at 0 C. the product was collected by filtration, washed with 7 water and dried. This solid'was uspended 'in500 ml. of

pyridine, warmed to 30 C. and filtered. 150 ml. of acetic washed and dried to give 52.68 g. (74% yield) of acetate (IV) with a melting point of 187 to C. Two

recrystallizations from acetone and Skellysolve B"(hex- L anes) raised the melting point to 198199 C. Y I

4nal.-Calcd. for cg n o to, 66.94; H, 8.09 'Foundi C, 66.75; H, 7.99. The infrared spectrum suppo 'rt the Y assigned structure. V V

Following the procedure of Example 1, but substituting 17.52010:21-bismethylenedioXy-2emethyl-4 pregnene 1 3,11-dione (Preparation 2) as the starting steroid, thereis thus produced 17 20,20: 21-bisinethylenedioxy 2m-rn' thyl- 5-pregnene-3 illfi-diol 3-acetate (IV). j

, Following theprocedure of Example 1, but's'ubstituting 7 17 20,20 :21-bismethylenedioxy- 1 6ce-methyl-4 pr gnene' 3,11-dione (Preparation '3 as the starting steroid, there H is thus 1 produced crystalline 17 20,20i21-bismethylenedioxy l 6u-methyl-51-p1 egnene-3B, 1 l ,B-diol B-acetate (IV Following the procedureiof Example 1, but substituting 17 :20,20:21 bismethylenedioxy-16fi-methyl-4-pregnene 3,11-dione .(Preparation'4) as the startingsteroid, there his thuspoduced 17:20,20:21 1 bismethylenedioxyamfl methyl-5-pregnene-'3,1le-diol 3 acetate (IV).

EXAMPLE 2 1 7:20,20:21-bisme!hylenedi0xy-1lfl-hydroxy-6ot-hydroxymethyl-oz-pregnane 3-zzcetate (V) A2000 ml. autoclave was charged with 36.4 g. of 17:20, :21-bismethylenedioxy-S-pregnene-3B,115 diol 3-acetate (IV), 1150 ml. of toluene and'9.1 g. of'cobalt carbonate. After flushing the-autoclave three times with car bon monoxide, the carbon monoxide pressure was raised to 650 pounds per square inch, and hydrogen was introduced until the gas pressure reached 1360 pounds per square inch. The reaction mixture in the autoclave was heated at 180 C. with agitation for a period of about 18 hours. The gases were vented and the reaction mixture removed from the autoclave. Following filtration through Celite (diatomaceous earth) the toluene was evaporatedin vacuo and the residue boiled for 1 hour in 1000 ml. of ethanol. The solution was filtered through Celite and the alcohol evaporated in vacuo. Crystallization of the residue from a mixture of acetone and Skellysolve B gave 15.8 g.

(crop #1) of 17:20,20:2 1-bismethylenedioxy-6a-hydroxymethyl-Sa-pregnene-BBJlfi-diol 3-acetate (V) with a melting point of 193 to 199 C. The mother liquors were chromatographed on a column of synthetic magnesium silicate, and eluted with acetone:Skellysolve B mixtures of increasing polarity. Elution with 2030% acetone:

.Skellysolve B gave an additional amount of 17 :20,20:21-

bismethylenedioxy-6m-hydrQXymethyI-Sa pregnene 3,8, 11 fl diol 3-acetate. Crystallization of the combined fractions from acetonezSkellysolve B gave a further 4.9 g. (crop 2) of product with a melting point of 193 to 199 C. Two crystallizations'from acetonezSkellysolve B yielded purified 17:20,20:ZI-bismethylenedioxy 6a hydroxymethyl-5a-pregnane-3BJ1fi-diol 3-acetate (V) having a melting point of 202 to 204 C.

Analysis.Calcd. for C H O C, 64.98; H, 8.39. Found: C, 64.63; H, 8.65. The infrared spectrum provided confirmation of the assigned structure.

Following the procedure of Example 2, but substituting 17:20,20:21 bismethylenedioxy-h-methyl 5 pregnene- 3,8,11,8-diol S-acetate as the starting compound, there is thus produced 17:20,2022l-bismethylenedioxy 2a methyl-6a-hydroxymethyl-Sa-pregnane-SB,11p-diol 3-acetate (V).

Following the procedure of Example 2, but substituting 17:20,20:21-bismethylenedioxy-16a-methyl-5 pregnene- 36,11fl-diol S-acetate as the starting compound, there is thus produced crystalline 17z20,20:21-bisrnethylenedioxy- 16a-methyl-6a-hydroxymethyl-5ot-pregnane-3 5,1 1,8-diol '5- acetate (V); substitution of the 16,8-methyl isomer as startting material yields 17 :20,20:2l-bismethylenedioxy-l6y3- methyl-6 a-hydrOXymethyI-S a-pregnane-3 8,1 lfi-diol 3 -acetate (V).

In the same manner as in Example 2, but substituting another 3-acylate for the starting 17:20,20:21-bismethylenedioxy-5-pregnene-3fi,1LS-diol 3-acetate. there is thus produced the corresponding 17:20,20:21-bisrnethylenedioxy-Gm-hydroxyrnethyl-5u-pregnane3 ,8,11,B-diol 3 acyl ate (V).

EXAMPLE 3 dihydroxy-Su-pregndne (VI) 1.2 g. of 17:20,20:21-bismethylenedioxy-6a-hydroxymethyl-5u-pregnane-3/3Jlfl-cliol 3-aceta'te (V); 1.2 g. of p-toluenesulfonyl chloride and 20 ml. of pyridine were allowed to stand at room temperature for a period of about 18 hours- The reaction mixture was then poured into sodium bicarbonate solution and the organic material extractedwith benzene. The extracts were washed succes- 14. sively with water, ice-cold dilute sulfuric acid, water, sodium bicarbonate solution, water and then dried with sodium sulfate. Removal of the solvent gave a light colored crystalline tosylate, which on recrystallization from a mixture of acetone and SkellysolveB yielded 1.25 g. of product with a melting point of'200 to 208 C.

1.2 g. of the tosyloxymethyl derivative, 17:20,20:21-bis-- 1 methylenedioxy-a-(p toluenesulfonoxymethyl) -5a pregnane-3B,11,B-diol S-acetate with a meltingpoint of 200.

to 208 C., 2.0 gjof anhydrous potassium fluoride and 20 ml. of diethylene' glycol. were heated with stirring at'a temperature of 205 to 215 C., under nitrogen for about 1 hour. After. cooling, 20 ml. of dioxane and a solution prepared from 0.5 g. of potassium hydroxide in 10 mLbf water were added tothe'reaction mixture and the result-- ing solution allowedto stand at room temperature for a period of about 18 hours. The reaction mixture was poured into Water and extracted with ethyl acetate. The combined extracts were washed with water until neutral, dried with sodium sulfate and the solvent removed. The residue'was dissolved in 25 ml. of methylene chloride and chromatographed on a column of g. of Florisil synthetic magnesium silicate and the column eluted with mixtures of acetone and Skellysolve B of increasing polarity.

rystalline material was obtained from 2030% acetone:Skellysolve B eluates. These were combined and recrystallized from methanol to give 240 mg. (crop 1) of 17 :20,20:21-bismethylenedioxy-6a-fiuoromethyl 5apregnane-3fl,1'1B-diol (VI) with a. melting point. of 215 to 217 C." Crystallization of the mother liquors from acetone:Skellysolve.B gave 140 mg. (crop 2) with a melting'point of 215 to 217 C. and mg. (c-ro p 3) wit=h a melting point of 213 to 215 C. of the same product. The infrared spectra of all crops were the same and the total yield was 51.0 mg. (61% yield). Further recrystallization from acetonezSkellysolve B yielded purified 17:20,20:ZI-bismethylenedioxy 6a fiuoromethyl 50:- pregnane-3,B,115-diol (VI) having a melting point of .217 to 219 C.

Analysis.Calcd. for C H O F: C, 65 .45 ;'H, 8.41; F, 4.32. Found: C, 65.08; H, 8.21; F, 4.57. The infirared spectrum supports the assigned structure.

Following the procedure of Example 3, but substituting 17:20,20:21-bismethylenedioxy-2a-methyl-6u hydroxymethyl-5a-pregnane-3/3,1lfi-diol 3-acetate as the starting compound, there is thus produced 17:20,20:21-bismethylenedioxy-6a-fluorQmethyI-Zu-methyI-SO; pregnane 3,8, 11,8-dio1 (VI).

Following the procedure of Example 3, but substituting 17:20,20:21-bismethylenedioxy-16a-methyl-6u hydroxymethyl-5u-pregnane-3fi,1lfi-diol 3-acetate as the starting compound, there is thus produced crystalline 17:20,20:21-

bismethylenedioxy-6u-fiuoromethyl-16a-methyl-5a pregnane-3B,'11B-diol (VI).

Following the procedure of Example 3, but substituting 17 20,20 2 1 -bismethylenedioxy-1 6fi-metl1y1-6a hydroxymethyl-5a-pregnane-3B,11B-diol 3-acetate as the starting compound, there is thus produced 17:20,20:21-bismethylenedioxy-6ot-fluoromethyl-16B-methyl-5a pregnane 3,3,

lle-diol v1 EXAMPLE 4 1 7:20,20:21 1iismethylenedioxy-6a-fluorometliyl- I1,BJzydroxyJa-pregnan-S-one (VII) 380 mg. ,of 17:20,20:21-bismethylenedioxy-6a-fiuoro 'methyl-Sa-pregnaneflllfi-diol (VI), 20 ml. of cycle-hex anone andv 30 ml. of toluene were placed together in a flask and heated until about 10 ml. of distillate was collected. 500 mg. of aluminum isopropoxide was added and the mixture refluxed for 4 hours. organic layer was washed first with ice-cold dilute hydrochloric acid, then with water until the washings were neutral, dried with sodium sulfate and the organic solvents re-v After cooling, the

moved by steam distillation. After cooling at C. "the solid. material was collected by filtration, washed and dried to give 380 mg. of product'having a melting point of 190 to 205 C; Crystallization from a mixture of ace- )tone and Skellysolve B hexanes gave 240 mg. of a light coloredcompound with melting point of 208to 212 C; 7

An additional crystallization from the same solvent mix- V ture yielded'purified crystalline 17:2O,20:21 bismethylenedioxy a 696- fluoromethyl-l1B-hydroxy qE-pregnan-3-one .(VII) having a'meltingpoint*of'211-2l3". C; i

.Arlal. Calcd. .for" 0 13 0 1 5 0, 65.75; 7.99; 5F, 4.34;" Found: C, 65.74; H, 8.19; F, 4.53. l

Following" the procedure of Example '4,--but substituting (1 17 220,20 2 l bisn iethylenedioxy-6o fluoromethyl-2umethyl-5u'-pregnane-3}8,1lfi diol (2): 17: 20,20 :2 1-bismethyleneclioxy 6m-flu oromethyl-l 6 a-methyl-Scxre gn ane-3 [3,

llB-diol and (3) 17:20,20:2l-bismethylendioxy-6c-fluoromethyl a16fl-methyl-5wpregnane-3fi11,8-diolf as starting compounds, 'there are thus produced, respectively (1) 17:20,20:21 bismethyleneclioxy 60c fluoromethyl-2lxmethyl-hydroxy-Sa-pregrian-3-one (VII); (2) l7:20 ,20:. 21 bismethylenedioxy 6tx-fluoromethyl 16m-methyl-11,8 hydrQXy Saregn-an-3 one (VII) and ('3) 17:20,'20: 21 bis droxy.-5lx-pregnan'-3 one (VII) V EXAMPLE 5 J7 20,20:21-bismethylenedion-d fluoromethyl- 11fi-hydroxy-I,4-preg zadiell-3-one (VIII) 200 mg. of 17 :20,20l21 bismethylenedioxya6oafiuoro methyl-11,8-hydroxy-5a-pregnan-3-one (VII), 400 mg. of selenium dioxide, 01mlofacetic acid andZOml; of tertiary butanol were heatedtogether under reflux for a period of about 48 hours. After the first 24 hours of reflux ing, 400 mg. of selenium dioxide was added to the reaction mixture and the-same amount again added about hours later. After cooling the mixture was filtered through Celite (diatomaceous earth) and -Magnesol (synthetic magnesium silicates). The filtrate'was evaporated to dryness and the residue taken up .in-ethyl acetate, which was washed successivelywith potassium bicarbonate solution,

freshly prepared ice-cold ammonium sulfide 'solution, icecold ammonia, dilute. hydrochloric acid, potassium bicarbonatesolution, water and dried with sodium sulfate.

' bonate (100 mg. in 10ml. ofrwater also ipurged with nitrogen) added and the resulting solution stirred-for about, '48 hours at'rooni temperture. Acetic acid was jadded to the solution until the pH was 7.0 andthe solventiremovedunder vacuum. The organic material wasremovedfrom Evaporation of the ethyl acetate gave 281' mg. of a crystalline solid, which was dissolved'in methylenechloride and chromatographed on a 20 geolumn of Florisil previously 7 V wetted with Skellysolve B and the column eluted with acetone:hexane of increasing polarity. 93 mg. of crystalline rnaterial was obtained frornthe to %lzicetonezSkelly .a solve B hexane eluates; crystallization from a mixture of acetone and Skellysolve B yielded 67 mg.- of 17:2O,2( ):2l-

" bismethylenedioxy fiuoromethyl 11,3 hydroxy-1,4-

pregnadien-3-one (VIII) with a melting point 'of 255 to 265 C. This material demonstrated an infrared spectrum in keeping with the structure postulated for the compound.

Ai mlreCalcd. for C H FO C, 66.36; H, 7.14. Found: C, 66.40; H, 7.41. V 7 Following the procedure of Example 5, but substituting (1)-"17: 20,20:21 bisrnethylenedioxy-6a-iluoromethyl 2amethyl-llB-hydroxy-Sa-pregnan-iisone; (2) 17 20,20: 2l-' bisme thylenedioxy 6a fiuoromethyl-l6a-methy-llB-hydroxya5lx-pre'gnan-3-one and (3) 17:20,20:'21'-bisniethyl 1 enedioxy 6w fluoromethyl-16B-methy-llfi hydroxyda- 1 pregnan-3-one as'starting compounds, there arethus pro 7 a duced, respectively, (I) l7:20,20:2l bismethylenedioxyone (VIII), (2) 17:20,20:2l-bismethylenedioxy-6u-fiuoro methyl 16oz methy- 11,8-hydroxy-1,4-pregnadien3-one SkellysolVe B yielded 248 mg. of. 6a+fluoromethyl-1 l S, '1704,211-trihydroxy 1,4-pregnadiene-3,20-dione .Qfl acetate 1 Y 5 (DC) with a melting ,point of 226 to 229? C." An additional; crystallizationfrom the same solvents -=producedj purified product with a melting point of .23 1-: to 233 C. '1

- The infrared spectrum exhibited by this compound sup- V (VIII) 'and'(3) 17220,20:21abismethylenedioxy-6a fluoromethyl 16 8 methyl f1lp-hydroxy-1,4-pregndien-3-0ne VHI). Z

I "AnaL -Calcd. for (3241 1311 0 ExAMrLlz 6 3,20-dipne (IX) g I Nitrogenwas bubbled through .lOlml. 'of.6.0%f ormic acid solutiorlduring 5 minute of heating 0a; asteam'bath.

Then 60 mg'. of l7:20,20:21rbisrnethylenedioxya6a flu'oromethyl 11B hydroxy-1,4-pregnadien-3-one (VIII) was added to'the hot formic acid while heating onthe steam bath was continued for 15-minutes, during which period nitrogen was continuously introduced, After cooling, the solution was poured into ice:sodiumbicarbonate solution and the organic material; extracted with methylenechlo-gf ride. The extract was washed with water, dr i'ed.with so dium sulfate and the solvent evaporated. The'crystalline solid' weighing 57 mg was dissolved in ZO-mlimetha'nol V previously purged for a period of about 20 minutes ,with

nitrogen) and an aqueous'solution of potassium bicarthe residue with methylene chloride; the extract dried with sodium sulfate. and evaporated to give 58 mg. of crystal-T line material. This was dissolved in a mixture of methylene'chlo'ride and ethyl acetate. and chromatographe d on a column'of 5.0 g. of Florisil synthetic magnesium silicate previously wettedwith Skellys'olve B hexanes; Light col-: 7 ored crystals were obtained from the 30% acetonez'Sklly-f solve B eluates. These fractions'werepooled and'crys'tal-i' lized from a mixture of acetone and Skellysolve B to giveg 19 mg. of 6d-fluoromethyl-11B,170:,2letrihydroxy-lA-preg j a meltingpo'int; of 232 to na'dierle-3,20-dione .(IX) with 235 C.

AnaL-Calcd. for a a r e, 67.35; H, 7.4; E435;-

Found: C,67.77; H, 7.95; F, 5.24.

Following the procedure of Example 6, buts'ubstituting (1) 17:20,20':21 bismethylenedioxy 6oz fiuOrOrnethY-Z- methyl-1 lfi-hydroxy-l ,4-pregnadien-3-one, (2) 1720,20; 21 bismethylenedio'xy. 6a-fiu'oromethylal fi c-methyl-l 1,8- hydroxy-l,4-pregnadien-3-one and (3) I17:20,20:21-'bisdroxy 1,4-pregnadien-3-one as starting compounds, there are thus produced, respectively, (1) 6q-fluoro-2-methyl 1 pregnadiene-3,20-dione (IX) was allowed to stand over-V night a t room temperature in 10 ml. of .P'yridine'containing 2.5 ml. of acetic anhydride. Afte r '18'hours at 7 room temperature the reaction mixture was poured into a mixture of :iceand sodihm bicarbonate solution and extracted with ethyl acetate. The pooledextracts were washed successively with water, dilute sulfuric TQCICL' water untilneutral anddried with sodium sulfate; Re: movalof the sol-vent gave a crystalline light-colored solid, which on recrystallization from a mixture of acetone and ports the assigned'structurev C, 6656;. 4.38.""Found:;C,-:66.23;IH, 7.34; F, 4.81.

. 6oz fluorc-meth yl '11B,17a,21-tri-hydroxy 1,4pregnaa 17 diene-3,20-dione (H) is converted to other ZI-esters by reaction with the appropriate acid anhydride, acid chloride or bromide, or by other methods known in the art, e.g., by ester exchange, acid in the presence of an esterification catalyst, etc., to produce 6oz-fluoromethyl-l1B,17e, 21 trihydroxy l,4-pregnadicne-3,ZO-dione 2l-acylates (IX') which include those wherein the acyl radical of the 21-acylate group is the acyl radical of, for example, a lower-aliphatic acid, e.g., formic, propionic, butyric, isobutyric, valeric, isovaleric, trimethylacetic, 2-methylbutyric, 3- ethylbutyric, hexa-noic, diethylacetic, triethylacetic, heptanoic, octanoic, a-ethylisovaleric, a cyclic acid, e.g., cyclopropylideneacetic, a cycloaliphatic acid, e.g., cyclopentylformic, cyclopentylacetic, fi-cyclopentylpropionic, cyclohexylformic, cyclohexylacetic, fl-cyclohexylpropionic, an aryl or alkaryl acid, e.g., benzoic, 2, 3, or 4-methylbenzoic, 2,3-, 2,4, 2,5-, 2,6, 3,4- and 3,5-dimethyl-benzoic, a-naphthoic, 3-methyl-a-naphthoic, an aralkyl acid, e.g., phenylacetic, phe-nylpropionic, diphenylacetic, triphenylacetic, a dibasic acid (which can be converted to water soluble, e.g., sodium salts), e.g., succinic, glutaric, a-methylglutaric, B-methylglutaric, 5,;8-dimethylglutaric, adipic, pimelic, suberic, a hydroxy acid, e.g., glycolic, lactic, citric, tartaric, d-maleic, d-glyceric, mannonic, gluconic, salicylic, 2,3,4-trimethoxybenzoic, a-naphthoxy-acetic, or other acyl acid.

Following the procedure of Example 7, but substituting 1) 6u-fluorornethyl-2-methyl-1'1fi,'17u,21-trihydroxy- 1,4 pregnadiene-3,20-dione, (2) 6a-fluoromethyl-16amethyl 11B,l7cc,2l tn'hydroxy-l,4-pregnadiene-3,20- dione and (3) 6a-fluoromethyl-l6fl-methyl-l1,8,17a,21- .trihydroxy-l,4-pregnadiene-3,20-dione as starting compounds, there are thus produced, respectively, (1) 60!.- fluoromethyl 2 methyl-l1,8;l7oz,21-trihydroxy-l,4-pregnadiene-3,20-dione 2l-acetate (IX), (2) 6oz-fluoromethyl- 16m methyl 11 18,17 :,21 trihydroxy l,4.- pregnadiene- 3,20-di0ne ill-acetate (IX') and (3) 6a-fluoromethyl 16B methyl-1 15-,l711,21-trihydroxy-1,4-pregnadiene-3 ,20- dione 2l-acetate (IX').

Similarly, 60c fluoromethyl-Z-methyhl1-fi,17a,2ltrihydroxy-l,4-pregnadiene3,20-dione, 6oz fluoromethyl-16amethyl-1lB,'17a,2l-trihydroxy 1,4 pregnadiene-3,20-dione and fiat-fluoromethyl 165 methyl-1 1fi,-17a,-21-trihydroxy-l,4-pregnadiene-3,ZO-dione are converted to any of the other esters named in the paragraph following Example 7 by substituting these compounds for Gut-fluoromethyl 11fl,17a,2-1 trihydroxy 1,4 pregnadiene-3,20- dione as the starting compound in the acyla-tion reaction.

EXAMPLE 8 6-flu0r0methyl-1IB,1 711,21 -trihydroxy-1 ,4,6- pregnatriene-3 ,2 O-dione 21-acezate (X) 60: fluoromethyl l1B,l7m,21-trihydroxyl,4pregnadiene-3,20-dione Zl-acet-ate (IX'), recrystallized 2,3,5,6- tetrachloro-l,4-benzoquinone (chloranil) and tertiary amyl alcohol were heated together to boiling under nitrogen with a few boiling chips and gently refluxed for a period of about 6 hours. The mixture was cooled and evaporated to dryness under reduced pressure. The solid residue with the exception of some insoluble chloranil was dissolved in ether and filtered. The ether filtrate was washed with cold 2% sodium hydroxide, cold Water (until the washings were neutral), then with saturated sodium chloride solution. The ether solution was dried over sodium sulfate and evaporated to dryness. The residue was readily crystallized from cold acetone to yield 6 fluoromethyl-1 15, 17a,2l-trihydroxy-1;4, 6-pregnatriene- 3,20-dione ZI-acetate (X).

The ester thus obtained can be hydrolyzed with potassium hydroxide or potassium carbonate in methanol or ethanol at room temperature in a nitrogen atmosphere to give the free triol, 6cz-fluoromethyl-l1,3,17a,21-trihydroxy- 1,4,6-pregnatriene-3,ZO-dione. The triol can be reesteritied to the 21-acylate by reacting it at room temperature in pyridine solution with the anhydride or acyl halide of an organic carboxylic acid.

In the same manner as in Example 8, substitution of Goa fluoromethyl-11,8,170:,21-trihyclroxy-1,4-pregnadiene- 3,20-dione as the starting steroid is productive of 6-fluoromethyl 1lB,17uz,21 trihydroxy-l,4,6-pregnatriene-3,20- dione.

Similarly, substituting as the starting steroid another 21-acylate of 6a-fluoromethyl-11B,l7ct,2l-trihydroxy-l,4- pregnadiene-3,20-dione for the 2l-acetate employed in the G-dehydrogenation reaction described in Example 8, wherein the acyl radical is, e.g., that of an acid named in the paragraph following Example 7, there is thus produced the corresponding 21-acylate of fi-fluoromethyll1fl, l7u,2il-trihydroxy*1,4,6-pregnatriene-3 ,ZO-dione.

Following the procedure of Example 8, but substituting 6a fluoromethyl 2-methyl-11,8,17a,21-trihydroxy-1,4- pregnadiene-3,20-dione 2'1-acetate, 6m-fl-uoromethyl-16umethyl-1 1,8, l7a,21-trihydroxy-1 ,4-pregnadiene-3,20- dione 2-l-acetate and 6a-fluoromethyl-lfi-methyl-l1,8,17e,21- trihydroxy-1,4pregnadiene 21-acetate as starting compounds, there are thus produced th corresponding "1,4,6- pregnatriene 2l-acetates (X).

Similarly, substituting as the starting steroids other 21- acylates of 6a-fluoromethyl-2a-methyl-l1 /3,17m,21-trihydroxy 1,4-pregnadiene-3,20-dione, 6a-fluoromethy1-l6amethyl 11fi,17a,21 trihydroxy 1,4-pregnad iene-3,20- dione and 6a fluoromethyl-16B-methyl-l1B,17a,2l-trihydroxy 1,4 pregnadiene-3,20-dione for the 21-acetate, there are thus produced the corresponding 1,4,6-pregnatriene 21-acylates.

EXAMPLE 9 17:20,.20:21-bismethylenedioxy-oa-fluoromethyl- 1I,B-lzydroxy-4-pregnen-3-one (X1) 250 mg. of 17:20,20:21-bismethylenedioxy6u-fluoromethyl-11fi-hydroxy-5u-pregnan8-one (VII) in 10 ml. of dioxane was acidified with one drop of 4 Normal hydrogen bromide in dioxane and 215 mg. of bromine added over a period of about 1 minute. After about 1 hour at room temperature an excess of sodium bicarbonate solution was added to the reaction mixture. The precipitated dibromo derivative of 17 20,20:21-bismethylenedioxy-6a-fluoromethyl-11fi-hydroxy-5a-pregnan-3-one (V11) was treated with 0.9 g. of sodium iodide in 15 ml. of acetone containing bromoacetone, and the mixture heated under reflux for about 2.5 hours. 0.3 g. of oxalic acid was then added and refluxing continued for a period of about 1 hour. After cooling, ethyl acetate was added and the solution filtered. The filtrate was washed with water and sodium bicarbonate solution, then dried with sodium sulfate. The filtrate was stirred with 500 mg. of zinc dust in 2 ml. of acetic acid for about 1 hour and filtered. The organic layer was washed successively with water, sodium bicarbonate solution and dried with sodium sulfate. Evaporation of the solvent gave the crude u,;8-unsaturated ketone, which on purification by means of the derivative formed with the Girard reagent, followed by subsequent crystallization yielded pure l7:20,20:21-bismethylenedioxy6afluoromethyl-11{3-hydroxy-4-pregnen-3-one (XI). Alternatively, if desired, the crude a,/5'-unsaturated ketone can be purified by chromatography over Florisil synthetic magnesium silicate with increasing proportions of acetone in Skellysolve B hexanes followed by recrystallization.

Following the procedure of Example 9, but substituting 1) 17 20,20 2 1-bismethylenedioxy-6a-fluoromethyl-2ctmethyl-1l,B-hydroxy-Sa-pregnan-3-one, (2) 17:20,20:21- bismethylenedioxy 6c: fluoromethyl 16a methyl- 1IB-hYdIOXY-Sm-plegDHH-3-OI16 and (3) 17:20,20:21-bismethylenedioxy 6a fluoromethyl 1613 methyl 11,8- hydroxy-5a-pregnan-3-one as starting compounds, there are thus produced, respectively, (1) 17:2(),20:21-bis methylenedioxy 20c methyl 11,8 hydroxy 4 pregnen- 3-one (XI), (2) 17:20,20:21-bismethylenedioxy-6a-fluoromethyl-la-methyl-llp-hydroxyt-pregnen-li-one (XI) V 19 and '(3) 17:20,20:21 bismethylenedioxy 6ot-fiuoromethyl l6/3-methyl 11p-hydroxy 4-pregnen-3-one (XI).

EXAMPLE 1O 120 mg. of 17:20,20:21-bismethylenedioxy-6a-fluoromethyl-1lB-hydroxy-4-pregnen-3-one (XI) was heated on a steam bath in 20 ml. of 60% formic acid for a period of about minutes while a stream of nitrogen was continuously passedthrough the solution. After cooling, the solution was poured into a mixture of ice and aqueous sodium bicarbonate and the organic material extracted with methylene chloride. The extracts .were washed with water, dried with sodium sulfate and the solvent removed by evaporation. The residuewas dissolved in 40 ml. of methanol previously purged with nitrogen. A solution of 200 mg. of potassium bicarbonate in ml. of water, previously purged with nitrogen, was added to the methanol solution and the combined liquids stirred for about 48 hours at room temperature. Acetic acid was added until the pH dropped to 7.01 and the solvent removed a under vacuum. The residue was extracted with methylene chloride; the extract was dried with sodium sulfate and then evaporated to give a solid. Purification of the solid, e.g., by recrystallization, yielded 6ct-fiuoromethyl-11 (3,171, 2l-trihydroxy-4-pregnene-3,20-dione (XII).

Following the procedure of Example 10, but substituting (1) 17 :20,20:21-bismethylenedioxy-6a-fiuoromethyl 20c methyl 1118 -v hydroxy 4 pregnen -3 one, (2) 17:20,20:21 bismethylene dioxy 60c fiuoromethyl- 2 l-trihydroxy-4-pregnene 3,20- dione. as starting com la-methyl-l1B-hydroxy-4-pregnen-3-one and (3) 17:20,

ExAMrLE 1 1 6a.-fluor0methyl-1 1,8,1 7a,21-trihydfoxy-4- V pregnene-3,20-di0ne (XII) V A medium consisting .of 1% dextrose hydrate, 27%

cornsteep liquor of 60% solids and tapiwater was adjusted to pH 4.9 with sodium hydroxide, The medium was stream sterilized at 15 pounds pressure'for 30 minutes, cooled, and then inoculated with'a 24-hour. growth, from spores, of NRRL B1332 (Streptomyces sp.). The medium was agitated, and sparged with sterile air at the rate of one-tenth volume of air per volume of medium per minute. At the end of 24 hours of fermentation at room temperature, the pH was about 7.4. To this culture there was added a solution of 6a-fluoromethyl-l1B,17 ,21-trihydroxy-l,4-pregnadiene-3,20-dione (1X) dissolved in a minimal amount of dimethylformamide. The solution Was prepared by dissolving five. parts of the steroid in 100 parts of the solvent and adding about 10 cc. of the solu- 'tion per liter of the medium. Fermentation was continued.

for a period of 48'hours whereupon the mycelium and beer were extracted thoroughly with methylene chloride. The extract was washed with sodium bicarbonate solution and then with water, dried and concentrated in vacuoto give 6u-fluoro-methyl-l l [3,17 a,2l-trihydroxy-4-pregnene- 3,20-dione (XII). i V

Instead of NRRL B-l332 used in Example 11 to produce fermentative hydrogenation at the 1,2-position of the steroid nucleus, other microorganisms may be similarly efiectively employed; included'are those chosen from the group consisting of: ATCC 6947 (Arthrobactertumescens); ATCC 3352 (S. olivaceous) and ATCC 3313.

. Following the procedure of Example 11, but substitub, ing (1) CL HHOIQmethYI-Z-IDQthYI-I lfi 3,l7a,21,-IihydIOX/.-

, a 20- 1,4-pregnadiene-13,20-dione, methyl l1 6,17 21 trihydroxy 1,4 pregnadiene 3,20- dione and (3) 6.qz-fluoromethyl-l6B-methyl-11,3,l7a,2 ltrihydroxy-l,4-pregnadiene-3,20-dione as starting compounds, there are thus produced, respectively, (1)

fluoromethyl 20c methyl l1]3,17oz,21.- trihydroxy 4 pregnene-3,20-dione (XII), (2) 6a-fluoromethyl-16mmethyl l1fi,17a,21 uihydroxy 4 pregnene 3,20- dione (XII) and (3) 6a-fluoromethyl-165-methyl 11B, l7u,2l-trihydroxy-4-pregnene-3,ZO-dione '(XII). '7

VEXAMPLE 12 3,20-diode ZI-zrcetate (XII') 7 1 Following the procedure of Example 7, but substituting 64x fluoromethyl 1l;3,17a,21 trihydroxy 4 pregnene- 3,20-dione (XII) as starting compound, there is thus produced 6d fluoromethyl -;11fi,17oc,21 trihydroxy 7 4- pregnene-3,20,-dione Zl-acetate (XII').

'Following the procedure of Example 7, butsubstituting 60c lluoromethyl-l1,8,170:,2l-trihydroxy-4-pregnene- 3,20-dione (XII) as starting compound, other 2l-acylates corresponding to those named in Example 7 are produced. a Following the procedures of Example 7, but substitute ing a 1) 6a fluoromethyl Zu-methyI-I lB,17a,21-trihydroxy 4 pregnene 3,20-dione, (2) vGan-fluoromethyh- 16a methyl 1lfi,17a,21 trihydroxy. 4 7 pregnene- 3,20-dione' and (3) 6oc-fiuoromethyl-16,8-methyl-115,l7a,

pounds, there are thus produced, respectively, the corresponding Zl-acetates and other 21-acylates thereof as named in Example 7. a 1

EXAMPLE 13 6-flu0r0methyl 175,17a,21 trihydroxy 4,6 pregna diene 3,20 dione 21-acetate (XIII) 6pc fluoromethyl 11,8,170 21 trihydroxy -.4 -.pregnene-3,20-dione ZI-acetate (XH'), recrystallized chloranil and tertiary amyl alcohol'were heated to boiling under nitrogen and refluxed for about 6 hours. Thereaetion mixture was cooled, evaporated to dryness; the residue (with the exception of chloranil, which is insoluble) dissolved. in ether and filtered. The ether filtrate was washed twice with cold 2% sodium hydroxide, cold water,

saturated sodium chloride solution; dried overfsodium sulfate and evaporated to dryness. .The residue crystal lized readily from cold acetone to give 6-fluoromethyll 1 8, 17:1,21-trihydroxy-4,6-pregnadiene- 3,20-dione 21-acetate (XIH). I V r The esters thus obtained can be hydrolyzed with potassium carbonate in methanol or ethanol at room temperature in an atmosphere of nitrogen to yield 6-fluoromethyl- 11B,170:,2l-trihydroxy-4,6-pregnadiene-3,20 dione. The

triol can be reesterified to form the 21-acy-late desired by by reacting at room temperature in pyridine with the.

anhydride or acyl halide of an organic carboxylic acid as disclosed in the paragraph following Example 7.

In the same manner as in Example 13, substitution of dione as the starting compound is productive of 6-fluoromethyl-l 15,1711,21-trihydroxy-4,6-pregnadiene-3,ZO-dione. Similarly, substituting as the starting steroid,' another pregnene-3,20-dione for the 2l-acetate employed in the 6-dehydrogenation reaction described in Example 13,

V wherein the acyl radical is, e.g., that of an acidnamed in the paragraph following Example 7, there is thus 'pro-' duced the corresponding 21-acylate of 6-fiuoromethyll1B,17c,21-trihydroxy-4,6-pregnadiene-3,20-dione.

Following the procedure of Example 13, but substitut ing 60c fiuoromethyl-2a-methyl-11fi,l7a,21 trihydroxy-4- pregnene-3,20-dione 2l-acetate, 60c fluoromethyl 16amethyl-.1 1,8,17u,21-trihydroxy-4-pregnene-3,20 dione 21- 21 acetate and 6e-fluoromethyl-16/3-methyl-11 5,17 u,21-trihy droxy-4-pregnene-3,20-dione 21-acetate as starting compounds, there are thus produced the corresponding 4,6- pregnadiene 21-acetates (XIIE).

Similarly, substituting other ZI-acylates instead of the 2l-acetates employed as starting compounds in the preceding paragraph, there are thus produced the corresponding 4,6-pregnadiene 21-acylates.

EXAMPLE 14 6 fluoromethyl 11,8,17u,21 trihydroxy 1,4,6 pregnatriene-3,20-dine 21 acetate (X) A medium consisting of 1% dextrose hydrate, 2% cornsteep liquor of 60% solids and tap water was adjusted to pH 4.9 with sodium hydroxide. The medium was steam sterilized at 15 pounds pressure for 30 minutes, cooled, and then inoculated with a 24-hour growth, from spores, of Septomyxa afiinis, ATCC 6737. The medium was agitated, and sparged with sterile air at the rate of one-tenth volume of air per volume of medium per minute. At the end of 24 hours of fermentation at room temperature, the pH was about 7.4. To this culture there was added a solution of 6u-fluoromethyl-11B, 170:,21-t.rihydroxy-4,6-pregnadiene-3,20-dione 21 acetate (XIII) dissolved in a minimal amount of dimethylformamide. The solution was prepared by dissolving five parts of the steroid in 100 parts of the solvent and adding about cc. of the solution per liter of the medium. Fermentation was continued for a period of 48 hours whereupon the mycelium and beer were extracted thoroughly with methylene chloride. The extract was washed with sodium bicarbonate solution and then with water, dried and concentrated in vacuo to give 6-fiuoromethyl-l1,8,17a,21-trihydroxy-1,4,6 pregnatriene 3,20- dione.

6 iuoromethyl 1l,8,17a,21 trihydroxy 1,4,6 preg natn'ene-3,20-dione dissolved in pyridine and acetic anhy dride was heated at 40 C. for about 4 hours. The reaction mixture was cooled, diluted with water .and the precipitate that formed removed by filtration. The precipitate was washed with water and dried to give 6a-fluoromethyl 11B,17e,21 trihydroxy 1,4,6 pregnatriene- 3,20-dione 21-acetate (X).

Carrying out the procedure of the method disclosed in Example 7 for the preparation of 21-acylates in addition to the 21-acetate, but substituting 6-fluorornethyl- 11B,17c,21 trihydroxy 1,4,6 pregnatriene 3,20- dione as starting compound, there is thus produced the corresponding 6 fiuoromethyl 11B,17a,21 trihydroxy- 1,4,6-pregnatriene 21-acylates.

Following the procedure of Example 14, but substituting 6-fiuoromethyl-2u-methyl-l1fl,17a,21-tril1ydroxy-4,6- preguadiene-3,20-dione 21-acetate, 6-fluoron1ethyl- 16ccmethyl 11B,17ec,21 trihydroxy 4,6 pregnadiene-3,20- dione ZI-acetate and 6-fiuoromethyl-16,8-methyl-115,17, 2l-trihydroxy-4,6-pregnadiene 3,20 dione as starting compounds, there are thus produced the corresponding 21-hydroXy-1,4,6-pregnatrienes. These 21-hydroxy compounds can be converted to their 21-acetates by heating with pyridine and acetic anhydride at about 40 C. for a. period of about 4 hours. The alcohols can be reesterified to form 21-acylates in addition to 21-acetates by reacting them at approximately 40 C. in pyridine with the desired anhydride of an organic carboxylic acid named in the paragraph following Example 7.

EXAMPLE 60c fluoromethyl 11,8,17oc-21-trihydr0xy-1,4-pregnadiene-3,20-dione 21-acetate (IX) Following the procedures of Example 14, but sub stituting the corresponding 4-pregnene compounds (XII') for 4,6-pregnadienes (X111) as starting steroids, there are thus produced the respective 1,4-pregnadienes, e.g., 6a-

22 fiuoromethyl 1l,6,17a,21 trihydroxy 1,4 pregnadiene- 3,20-dione 2l-acetate and 6u-fiuoromethyl-2-methyl-11B, 17,2l-trihydroxy-1,4pregnadiene-3,20-dione 21 acetate (IX') instead of 6-fiuoromethyl-11fl,17a,21-trihydroxy- 1,4,6-pregnatriene-3,20-dione 21-acetate and 6 fluoromethyl-Z-methyl-llfi,17a,21-trihydroxy 1,4,6 pregnatriene-3,20-dione 21-acetate (X).

- EXAMPLE 16 6 u-fluoromethyl-l 76;,21 -dihydr0xy-4-pregnene- 3,11,20-tri0ne 21-acetate (XV) To a solution of 6afiuorornethyl-llB,17a,21-trihydroxy-4-preguene-3,ZO-dione 21-acetate (XII' and XIV), and pyridine in tertiary butanol was added Ndaromoacetamide. The reaction mixture was maintained at room temperature for a period of about 16 hours, diluted with Water containing about 1% sodium sulfite and the mixture concentrated under reduced pressure to a small volume. The distillation residue was refrigerated, filtered, the filter cake washed with water and dried. It consisted of 6a-fluoromethyl-170:,2l-dihydroxy-4-pregnene-3,11,20- trione ZI-acetate (XV).

Following the procedure of Example 16, but substituting 60: fluoromethyl-2a-rnethy1-1lfl,17a,21-trihydroxy-4 pregnene 3,20 dione 21-acetate, 6u-fluoromethyl-16w methyl-11,3,170:,21-trihydroxy3,2O-dione Ill-acetateand 60a fluoromethyl-l6fl-methyl-11B,17a,21-trihydroxy-3,20- dione 21-acetate as starting steroids, there is thus produced the corresponding ll-keto analogues (XV).

EXAMPLE 17 6oz-flu0romethyl-1 7 (1,21 -dihydroxy-1 ,4-pregnadime-3,11,20-trione 21 -ncetate (XV) Following the procedures of Example 16, but substituting the corresponding 1,4-pregnadienes (DC) for 4- pregnenes (XII') as starting steroids, there are thus produced the respective 1,4-pregnadienes, e.g., 6a-fluoromethyl-17a, 21-dihydroxy-l,4 pregnadiene 3,11,20 trione 21-acetate and 6a-fluoromethyl-2-methyl-17a,2l-dihydroxy-lA-pregnadiene-3,11,20-trione 21-acetate (XV) instead of 6afiuoromethyl 1704,21 dihydroxy 4 pregnene-3,11,20'- trione 2l-acetate and 6a-fluoromethyl-2a-methyl-170;,21- dihydroxy-4-pregnene-3,l1,20-trione 21-acetate (XV).

EXAMPLE 18 6-fluoromethyl-J 7 a,2] -dihydroxy-4,6 -pregnadiene-3,11,20-trione 21 -acetate (XV) Following the procedure of Example 16, but substituting the corresponding 4,6-pregnadienes (XIII) for 4- pregnenes (XII') as starting steroids, there are thus pro duced the respective 4,6-pregnadienes, e.g., 6-fluorometh yl-17a,21-dihydroxy 4,6 pregnadiene-3,l1,20-trione 21- acetate and 6-fiuoromethyl-2a-methyl-l7a,21-dihydroxy- 4,6-pregnadiene-3,11,20-trione 21-acetate (XV) instead of 6ct-fiuoromethyl-Hail-dihydroxy 4 pregnene-3,ll,20 trione 21-acetate and Ga-flUOl'OmEthYl-Za-methYl-l7ot,2l dihydroxy-4-pregnene-3,11,20-trione 21-acetate (XV).

EXAMPLE 19 6-flu0r0methyl-Z 7 01,21 -dz'hydr0xy-1 ,4,6- pregna- Merle-3,1 1,20-trione 21-acetate (XV) Following the procedure of Example 16, but'suhstituting the corresponding 1,4,6-pregnatrienes (X) for 4- pregnenes (XII') as starting steroids, there are thus produced the respective 1,4,6-pregnatrienes, e.g., 6-fiuoromethyl-l7zz,2l-dihydroxy 1,4,6 pregnatriene 3,11,20- trione 21-acetate and G-fluoromethyl-Z-methyl-17a,21-dihydroxy-1,4,6-pregnatriene 3,11,20 trione 21 acetate (XV) instead of 6a-fluoromethyl 1704,21 dihydroxy-4- pregnene-3,l1,20-trione 21-acetate and 6u-fluoromethyl- 2u-methyl-17a,2l-dihydroxy 4 pregnene-3,l1,20-trione 2l-acetate (XV).

EXAMPLE 27 6 u-fluorom ethy l-1 1,6,1 7a,21-trihydr0xy-9a-br0m0-1,4,6- pregnatriene-3,20-dii1e 21-acetate (XVII) Following the procedure of Example 24, but substituting the corresponding 1,4,6,9(11)-pregnatetraenes for 4,9(11)-pregnadienes as starting compounds, there are thus produced the respective 9a-bromo-4,6-pregnatrienes, e.g., 6-fluoromethyl-l1B,17a,21-trihydroXy-9u,bromo-1,4, 6-pregnatriene-3,20-dione 21-acetate and 6-fluoromethyl- 2 methyl 1lB,17x,21 trihydroxy 9a bromo,l,4,6, pregnatriene-3,20-dione 21-acetate (XVII) instead of 6a fluoromethyl 11B,l7cz,21 trihydroxy 9a-bromo-4- pregnene-3,20-dione 21-acetate and 6a-fluoromethyl-2amethyl-115,17a,21-trihydroXy-9aa-bromo4-pregnene 21- acetate (XVII).

Substituting for the 21-acetates of the starting steroids of Examples 24, 25, 26 and 27 other 2l-acylates wherein the acyl radical is that of an acid named in the paragraph following Example 7, as the starting compounds in the bromination reaction described in Example 24, there are thus produced the corresponding 21-acylates instead of the 2l-acetates of the 9a-bromo-4-pregnenes, 9cc-bromo 1,4-pregnadienes, 9rx-bromo-4,6-pregnadienes and 9abromo-1,4,6-pregnatrienes prepared in Examples 24, 25, 26 and 27.

Substituting N-chlorosuccinirnide for the N-bromoacetamide in the reactions described in Examples 24, 25, 26 and 27 is productive of the corresponding Qa-chloro compounds, .eg., 6m-fi1101'Omethyl-11fi,17u,21IIIhydI0Xy- 9a-chloro-4-pregnene-3,ZO-dione 21-acetate, 6oz-fl1101'0- methyl 1lB,l.7a,21 trihydroXy-9a,-chloro-1,4-pregnadiene-3,20-dione ZI-acetate, 6fluoron1ethyl-11,8},17a,21- trihydroxy-9zx-chloro-4,6-pregnadiene-3,20-dione 21-acetate, 6-fluoromethyl-11B,17a,2l-trihydroXy-9a-chloro-L4, 6-pregnatriene-3,20-dione 21-acetate and the Zea-methyl, lfioc-mefhyl and 16p-methyl derivatives of these compounds.

EXAMPLE 28 6a-flu0r0methyl-95J1,8-epoxy-1 7 a,21 -dihydr0xy-4-pregnene-3,20-dione 21 -acetate (XV III) To a solution of 7.0 g. of 6a-fl1l01'0m6thyl-11B,17a, 21-trihydroXy-9a-bromo-4-preguene-3,20-dioue 21-acetate in 200 ml. of acetone was added 7.0 g. of potassium acetate and the resulting suspension was heated under reflux for a period of about 17 hours. The mixture was then concentrated to a small volume at reduced pressure on the steam bath, diluted with water and extracted with methylene chloride. The methylene chloride extracts were combined, washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was redissolved in methylene chloride and chromatographed over Florisil synthetic magnesium silicate. The column was eluted with hexanes (Skellysolve B) containing increasing proportions of acetone. There was thus eluted 6afluoromethyl 95,113 epoxy 17a,21-dihydroxy-4-pregnene-3,20-dione 21-acetate (XVIII) which was freed of solvent by evaporation of the eluates.

Following the procedure of Example 28, but substituting 6e fiuoromethyl 20c methyl-l 1,8,17oc,Z1-111il1Y- droXy-9a-bromo-4-preg-nene-3,ZO-dione ZI-acetate, 6afluoromethyl 16oz methyl ll;9,17a,2l trihydroXy-9abromo-4-pregnene-3,20-dione 21-acetate and GOL-fiIIOI'O' methyl 16,8 methyl 1lB,l7ce,21-trihydroXy9m-bromo- 4-pregnene-3,20-dione 21-acetate as starting compounds,

there are thus produced, respectively, the corresponding 60: fiuoromethyl 2a-methyl-9B,11;3-epoXy-17a,21-dihydroXy-4-pregnene-3,20'dione 21-acetate, 6a-fluoromethyl- 16oz methyl 9,8,11/3 epoxy,l7u,21-dihydroXy-4-pregnene-3,20-dione 21-acetate and 6a-fluoromethyl-l6fimethyl 9,8,11,6 epoxy-17u,2l-dihydroxy-4-pregnene-3, 20-dione 21-acetate (XVIII).

EXAMPLE 29 6a-flu0romethyl-9BJ 1,8-epoxy,1 7a,21-dihydr0xy-1,4- pregnadiene-3,20di0ne 21-acetate (XVIII) Following the procedure of Example 28, but substituting the corresponding 9a-bromo-1,4-pregnadienes for 90:- bromo-4-pregnenes as starting compounds, there are thus produced the respective 95,1lfl-epoxy-1,4-pregnadienes, e.g., 6a fluoromethyl 9fl,l1,8-epoxy-17a,2l-dihydroxy-l, 4-pregnadiene-3,20-dione 21-acetate and 6a-fluoromethy1- 2 methyl -95,1lfl-epoxy-17,21-dihydroXy-1,4-pregnadiene-3,20-dione 21-acetate (XVHI) instead of 6a-fluoromethyl 9 8,1I a-epoxy-17a,21-dihydroXy-4-pregnene-3,20- dione 2l-acetate and 6a-fluorornethyl-h-methyl-17a,21- dihydroXy-4-pregnene-3,20-dione 21-acetate (XVIII).

EXAMPLE 30 Following the procedure of Example 28, but substituting the corresponding 9a-bromo-4,6-pregnadienes for 9abromo-4-pregnenes as starting compounds, there are thus produced the respective 9,8,11/S-epoXy-4,6-pregnadienes, e.g., 6-fluoromethyl-9,6,1Iii-epoxy-17a,2l-dihydroXy-4,6 pregnadiene-3,20-dione 21-acetate and 6-flIlOI'OIIIEIhYl-2OL- methyl-9,8, 1 1fl-epoXy-4,6-pregnadiene-3,20-dione 21-acetate (XVIII) instead of 6a-fluoromethyl-9fl,1lB-epoXy-4- pregnene-3,20-dione 2l-acetate and 6a-fiuoromethyl-2umethyl 95,115 epoXy-4-pregnene-3,20-dione 21-acetate (XVIII).

EXAMPLE 31 Following the procedure of Example 28, but substituting the corresponding,9a-bromo-1,4,6-pregnatrienes for 9a-bromo- 4-pregneues as starting compounds, there are vthus produced the respective 9,8,11fi-epoxy-1,4,6-pregnatrienes, e.g., 6 fiuoromethyl 9&11;S'-epoXy,17a,21-dihydroxy 1,4,6 pregnatriene 3,20-dione 2l-acetate and 6- fiuoromethyl 2-methyl-9fi,1lfi-epoxy-1,4,6-pregnatriene- 3,20-dione 2l-acetate (XVIII) instead of 6a-fluoromethyl 9,9,1LIB-epoxy-:,21-dihydroXy-4-pregnene-3,20- dione 21-acetate and 6a-fluoromethyl-Za-methyl-QB,11,6- epo y-17a,21-dihydroXy-4-pregnene-3,ZO-dione 21-acetate (XVIII).

Substituting for the 21-acetates of the starting steroids of Examples 28, 29, 30 and 31 other ZI-acylates wherein the acyl radical is that of an acid named in the paragraph following Example 7, as the starting compounds in the epoxidation reaction described in Example 28, there are thus produced the corresponding 21-acylates instead of the ZI-acetates of the 95,11B-epoXy-4-pregnenes, 918,115- epoXy-l,4 pregnadienes, 9,8,11B-epoxy-4,6-pregnadienes and 96,1lfi-epoxy-l,4,6-pregnatrienes prepared in Examples 28, 29, 30 and 31.

EXAMPLE 32 To approximately 1.3 g. of hydrogen fluoride contained in a polyethylene bottle and maintained at minus 60 C. was added 2.3 ml. of tetrahydrofuran and then a solution of 500 mg. of 6a-fiuoromethyl-9}9,11B-epoXy-17u,21-d.ihydroxy-4-pregnene-3,20-dione 21-acetate (XVIII) in 2 ml. of methylene chloride. The steroid solution was 29' fiuoro-4-pregnene-3,ZG-dione ZI-acetate, 6rx-fluoromethyll6a-methyl-l1B,17 x,2l trihydroxy-9a-fiuoro-4-pregnene- 3,20-dione ill-acetate and 6u-fluoromethyl-16fi-methyl- 1113,17a,21-trihydroxy-9a-fluoro 4 pregnene-3,20-dione ill-acetate as starting compounds, there are thus produced, respectively, the corresponding GcL-flHOIOIIlE'thYl-Zu-Dlfifllyl-17a,21-dihydroxy-9a-fiuoro-4-pregnene 3,11,20-trione 2 l-acetate, 6 a-fiuoromethyll 6ct-methyl-17a,2 l-dihydroxy- 9a-fluoro-4-pregnene-3,11,20-trione ZI-acetate and 60afluoromethyl-l6,8-methyl-17a,2l-dihydroxy 90c fluoro-4- pregnene-3,11,20-trione Zl-acetate (XX).

EXAMPLE 38 Following the procedure of Example 37, but substituting the corresponding 1,4-pregnadienes for 4-pregnenes as starting compounds, there are thus produced the respective l,4-pregnadiene-3,11,20-triones, e.g., 6a-fluoromethyl 17 u,21 dihydroxy 91x fiuoro-1,4-pregnadiene- 3,11,20-trione ZI-acetate and 6u-fiuoromethyl-2-methyl- 17a,21-dihydroxy 9a -fluoro 1,4 pregnadiene-3,11,20- trione 21-acetate (XX) instead of 6a-fluoromethyl- 170:,21-dihydroxy-9a-fluoro-4-pregnene-3,11,20trione 21- acetate and 6a-fluoromethy1-2a-methyl-17u,2l-dihydroxy- 9a-fluoro-4-pregnene-3,l1,20-trione 21-acetate (XX).

EXAMPLE 39 Following the procedure of Example 37, but substituting the corresponding 4,6-pregnadienes for 4-pregnenes as starting compounds, there are thus produced the respective 4,6-pregnadiene-3,11,20-triones, e.g., 6-fluoromethyl 170:,21 dihydroxy 9a fluoro-4,6-pregnadiene- 3,11,20-trione 2l-acetate and 6fluoromethyl-2a-methyl- 17a,21-dihydroxy-9u-fluoro 4,6 pregnadiene-3,11,20- trione 2l-acetate (FCC) instead of 6a-fluoromethyl- 170:,21-dihydroxy-9a-fiuoro-4-pregnene-3,11,2O-trione 21- acetate and 6a-fiuoromethyl-2u-methyl-17a,2l-dihydroxy- 9a-fiuoro-4-pregneue-3J1,20-trione 2l-acetate (XX).

EXAMPLE 40 Following the procedure of Example 37, but substi- T115112 the 001T Ponding 1,4,6-pregnatrienes for 4-pregnenes as starting compounds, there are thus produced the respective 1,4,6-pregnatriene-3,11,20-triones, e.g., G-fiuoromethyl 1701,21 dihydroxy 90c fluoro 1,4,6 pregnatriene-3,11,20-trione 21-acetate and 6-fluoromethyl-2- methyl 17a,2l dihydroxy 9a fluoro 1,4,6 pregna triene-3,11,20-trione 21-acetate (XX) instead of 6cz-fl110I0 methyl 1704,21 dihydroxy 90c fluoro 4 pregnene- 3,ll,20-t1'ione 21-acetate and 6oc-fluoromethyl-2u-methyl- 170:,21-dihydroxy-9a-fluoro-4preguene-3,11,2O-trione 21- acetate ()QQ.

Substituting for the ZI-acetates of the starting steriods of Examples 37, 38, 39 and 40 other 21-acylates wherein the acyl radical is that of an acid named in the paragraph following Example 7, as the starting compounds in the oxidation described in Example 37, there are thus produced the corresponding 2l-acylates instead of the 21-acetates of the 4-pregnene-3,ll,20-trione, 1,4-pregnadione-3,11,20- triones, 4,6-pregnadiene-3,11,20-triones and 1,4,6-pregnatriene-3,ll,20-triones prepared in Examples 37, 38, 39 and 40.

EXAMPLE 41 6a-flzt0romethyl-11 5117112] -trihydrxy-9a-fluoro- 4-pregnene-3,20-di0ne (XXI) Three grams of 6u-iluoromethyl-1l,8,l7u,2l-trihydroxy- 9a-fluoro-4-pregnene-3,ZO-dione 21-acetate (EX) was dissolved in 300 ml. of methanol, previously purged of airoxygen by passing nitrogen through it for 10 minutes and thereto was added 25 ml. of 5% aqueous solution of potassium bicarbonate, similarly purged of oxygen. The mixture was allowed to stand at room temperature for a period of about 5 hours in a nitrogen atmosphere, thereupon neutralized with acetic acid in water. The mixture was concentrated to approximately one-third volume at reduced pressure on a 60 C. water bath. Thereupon Water was added and the mixture chilled. The crystalline product was collected on a filter, washed with Water and dried to give 6a-iluoromethyl-1lfl,17a,21-trihydroxy-9afiuoro-4-pregnene-3,ZO-dione (XXI).

Following the procedure of Example 41, but substituting 6a-fluoromethyl-2a-methyl-l 1,8, 17 0:,21-lIlhYdl'OXY- 4-pregnene-3,20-dione 21-acetate, 6a-fluoromethy1-16amethyl 1l/3,l7oc,2l trihydroxy 9a fiuoro 4 pregnene-3,20-dione ZI-acctate and Ga-fiHOIOIHClhYl-IGB- methyl 11,8,17cz,2l trihydroxy 9a fluoro 4 pregnene-3,20-dione ZI-acetate OCIX) as starting compounds, there are thus produced, respectively, as light-colored crystalline solids 6a-fluoromethyl-2a-methyl-11B,17rx,21- trihydroxy-9a-fluoro-4-pregnene-3,20 dione, 6a fluoromethyl 16a. methyl 11,8,l7oc,21 trihydroxy 9a fluoro-4-pregnene-3,20-dione and 6a-fluoromethyl-16B- methyl 1l/8,l7oz,2l trihydroxy c fiuoro 4 pregnene-3,20-dione (XXI).

EXAMPLE 42 Following the procedure of Example 41, but substituting the corresponding 1,4-pregnadienes for 4-pregnenes as starting compounds, there are thus produced the respective 1,4-pregnadiene-3,20-diones, e.g., 6oc-fluoromethyl- 115,17a-21 trihydroxy 9a fiuoro 1,4 pregnadiene- 3,20-dione and 6a-fiuoromethyl-2-methyl-11,8,17a,2l-trihydroxy-9a-fluoro-lA-pregnadiene-3,20-dione (XXI) instead of 6a-fluoromethyl-11B,17a,21-trihydroXy-9a-fluoro- 4-pregnene-3,20-dione and 6a-fluoromethyl-2oc-methyl- 1 1B,17u,21 trihydroxy 90c fluoro-4-pregnene-3,20-dione (XXI).

EXAMPLE 43 6-fluoromethyl-1 1,8,1 711,21 -trihydr0.xy-9cc-fluor0- 4,6-pregnadiene-3,20-dione (XXI) Following the procedure of Example 41, but substituting the corresponding 4,6-pregnadienes for 4-pregnenes as starting compounds, there are thus produced the respective' 4,6-pregnadiene-3,20-diones, e.g., 6-fluoromethyl- 11B,l7oc,21 trihydroxy 90c fluoro 4,6 pregnadiene- 3,20-dione and 6-fluoromethyl 2a-methyl-115,17a,21- trihydroxy-9a-fluoro-4,6-pregnadiene-3,20-dione ()QCI) instead of 6u-fiuoromethyl-l113,17u,21-trihydroxy-9u-fluoro- 4-pregnene-3,20-dione and 6a fiuoromethyl-2a-methyll1B,l7oc,21 trihydroxy 9a fluoro-4-pregnene-3,ZO-dione (XXI).

EXAMPLE 44 Following the procedure of Example 41, but substituting the corresponding 1,4,6-pregnatrienes for 4-pregnenes as starting compounds, there are thus produced the respective 1,4,6-pregnatriene-3,ZO-diones, e.g., 6-fluoromethyl 1 1 [3,17 11,21 trihydroxy 90c fluoro 1,4,6 pregnatriene-3,20-dione and 6-fluoromethyl-2-methyl-11 8,17a, 21 trihydroxy 9a fiuoro 1,4,6-pregnatriene-3,ZO-dione (XXI) instead of 6a-fiuoromethyl-11B,17u,21-trihydroxy- 9a-fiuoro-4-pregnene-3,ZO-dione and 6u-fluoromethyl2amethyl 11 j3,l7a,2l trihydroxy 9a fiuoro 4 pregnene-3,20-dione (XXI).

Substituting for the 21-acetates of the starting steroids of Examples 41, 42, 43 and 44 other 21-acylates wherein the acyl radical is that of an acid named in the paragraph following Example 7, as'the starting compounds in the hydrolysis described in Example 41, there are thus proare i ducedthe 21-hydroxy'compounds prepared in Examples 41, 42, 43 and 44. 7 a

The corresponding 91x-chloro compounds are similarly prepared by hydrolysis of their ll-acetates, e.g., 6a-fiuor0-. methyl 11B,l7oz,21 trihydroxye 9a chloro 4 pregnene-3,20-.dione Zl-acetate, 6oc-fiuoromethyl-1lfi,l7a,2l-. tr'ihydroxy- 90c chloro 1,4 pregnadiene 3,20-dione 21-acetate, 6 fluoromethyl .11,B,17u,21 trihydroxy 90c: chloro-4,6-pregnadiene-3,20-dione 21-acetate and d-fluoro: methyl 11 3,17u,21 trihydroxy -.91z chloro 1,4,6 pregnatriene-3,20-dione 21-acetate are converted to their corresponding 21-hydroxy compounds... Following the procedures of Examples 41, 42, 43 and 44, the corresponding ll-keto compounds represented by Formula QQi are similarly hydrolyzed to their respective 21-hydroxy compounds. r

. 6oz fiuoromethyl 1l/3,17a,21 trihydroxy 4 pregnene-3,20-dione (XII) (prepared. as in Example .10) was dissolved in pyridine. This solution was cooled to C. and treated with methanesulfonyl chloride. Thereafter the solution was allowed to stand at 0 to C. for a period of about 2 hours, after which it was diluted with water and extracted with several portions of methylene chloride; 'The extracts were combined, washed with cold dilute hydrochloric acid until the aqueouslayer had a pH of two-to three, then washedagain with cold sodium bicarbonate solution, Water and finally dried over anhydrous sodium sulfate. Evaporation of the methylene chloride extract at reduced pressure left a residue of 6a fluoromethyl -l1B,17a,21 trihydroxy 4 pregnene- 3,20-dione 2l-methanesulfonate.(XX[l). a

Following the procedure of Example 45, but'substituting 6a-fiuoromethyl-2-a-methyl-11fi,17a,21-trihydroxy-4- pregnene-3,20-dione, ou-fluoromethyl-l6a-methyl-1 15,1711,

21-1Iihydroxy-4-pregnene-3,ZQ-dione and. 6m-fluoromethyllfifl-methyl-l 1B, 17:1,2 1-trihydroxy-4-pregnene 3,20-dione as starting compounds, there are thus produced, respectively, thejorresponding 6 og-fluoromethyl-2a-methyl-l15, 170:,2'1-trihydroxy-4-pregnene-3,20 dione 21-m'ethanesulfonate, 6a-fluoro-methyl-1Got-methyl 11fl,17oc,21 trihydroxy-4-pregnene-3,20-dione ZI-methanesulfonate and'6afiuoromethyl-16B-methyl-l1B,17a,21-trihydroxy 4 nene-3,20-dione Ill-methanesulfonatm r The corresponding 9a-fll101'0 and 9a-chloro ZI-methanesulfonates are similarly preparedby substituting 6cz-fill010- methyl-9a-fluoro 11 8,17a,21 trihydroxy 4 pregnene- 3,20-dione and 6a-fluoromethyl-9wchloro-11fi,17a,21-trihydroxy-4-pregnene-3,20-dione as starting compounds.

EXAMPLE 46 6a-flor0methyl-11B,]7a,21-trihydroxy-1,4-pregnrzdiene 3,20-dione 21 methanesulfonate (XXII) arsaeoa 7 EXAMPLE 47 13,20-di0ne ZI-methanesulfondt (XXII) Following the procedure of Example 45, but substitut ing the corresponding 4,6-preguadieues (XIII)f(prepared as in Example. 13) for 4-pregnenes asstarting compounds, 7

there are thus produced the respective 4,6-pregnadine-j 21-methane-sulfonates, e.g., -fluoromethyl-l1,8,17a,21-trihydroxy-4,6-pregnadiene-3,ZO-dione ZI-methanesulfonate and -fluoro-methyl-Zu methyl -i 11,8,170c,21 trihydroxy 4,6-pregnadiene-3,20-dione ZI-methanesulfonate (XXII) instead of 6oc-fluoro-methyl-' 1 1 53,1712l-trihydroxy-4 pregnene-3,20-dione 21-methanesultonate and 6a-fluoromethyl- 21-trihydroxy-4,6-pregnadiene-3,20-dione as starting com V Following the procedure of Example 45, but substituting the corresponding 1,4, 6-pregnatrienes (X) (prepared as in'Example 8) for 4-pregnenes as starting compounds,

there are thus produced the respective 1,4,6-pregnafi'iene 21-methanesulfonates, e.g., '6 fluoromethyl 11fi,17u,21-

trihydroxy-1,4,6-pregnatriene-3,20 dione 21-methanesul fonate and 6-fluoromethyl-2 methyl 11B,17oz,21 trihy-.

droXy-1,4,6-pregnatriene-3,ZO-dione '2'lmethanesulfonate (XXII) instead of'6og-fluoromethyl-1lB,17 c,2l-trihydroxy- 4-pregnene-3,20-dione 21-methanesulfonate and fia-fluoro-i methyl-2a-m'ethyl 1113,17cz,21 trihydroxy 4 pregnene 3,20-dione 2l-metlianesu1fonate ()OGI); I 4 T he corresponding 9u-fl11QIO and 9a-chloro 21-methanesulforiates are similarly prepared by substituting 6oz-fl11OIO-i pregneneei20-dione (XXVI) The crude 6a-fluoromethyl 11B,17a,21 trihydroxy-4- pregnene-3,20-di one 21-methanesulfonate (XXH) described in Example was dissolved in 15 ml. of acetone and treated with 10 ml. of a 12.5% solution ofsodium iodide in acetone. with stirring for a period of about 15 minutes, the heat then reduced and the mixture concentrated'toone-third volume at'redu'ced pressure. Ice and Water were added and the precipitated product collected on a filter, washed With water and dried to yield 6a-fluoromethyl-11fi,17udihydroxy-21-iodo-4-pregnene-3,20-dione (XXVI).

Following the procedure of Example 49, but substitut ing 6u-fluoromethyl-2 a-methyl 11B,17u,21-trihydroxy-4- pregnene-3,20'-dione ZI-methanesulfonate, 6u-fiuoromethyl-15a-methyl-11/3,17a,21 trihydroxy 4 pregnene 3,20 dione ZI-methanesulfonate and 6ocfluoromethyl-16;8-meth yl-11B,17a,21 trihydroxy-4-pregnene-3,ZO-dione 21-meth anesulfonate as starting compounds, there are thus produced, respectively, the corresponding 6a-fiuoromethyl 2ur methyl-11B,17a-dihydroxy 21 -'iodo 4 pregnene 3,20-

iodo-4-pregnene 3,20 dione and 60a fiuoromethyl 1618- methyl-1 l/i, l7a-dihydroxyr2l -iodo-4-pregnene-3,ZO-dione. The corresponding 9a-fluoroand 9a-chloro analogues of the compounds prepared in Example 49 are similarly produced.

The mixture was heated under reflux Following the procedure of Example 49, but substituting the corresponding 1,4-pregnadienes for .4-pregnenes as starting compounds,.there are thus produced the respective 1,4- pregnadiene 21 -iodides, e.g., 6m-fluoromethyl- 11p,17a-dihydroxy-21-iodo-L4 pregnad ene 3,20 dione and 6a-fluoromethyl-2-methyl-l l-B,l7a-dihydroxy*21-iodo- 1,4-pregnadiene-3,20-dione (XXVI) instead of 6a-fiuoro methyl-1 15,17rx-dil1Yd1OXY-Z 1-iodo-4-pregnene-3,20-dione, and GOC-flllOIOIHGthYl-ZOC methyl 115,170: dihydroxy-Zliodo-4-pregnene-3,20-dione (XXVI).

The corresponding 9a-fluoro and 9a-chloro analogues of the compounds prepared in Example 50 are similarly produced.

EXAMPLE 51 6-fluorometizy l-] 15,] 7m-dihydroxy-2l Jada-4,6- pregnadiene-3,20-a'ione (XXVI) Following the procedure of Example 49, but substituting the corresponding 4,6-pregnadienes for 4-pregnenes as starting compounds, there are thus produced the respective 4,6-pregnadiene 21-iodides, e. g., 6-fluoromethyl- 11,8,17a dihydroxy 21 iodo 4,6 pregnadiene ,20 dione and 6-fluoromethyl-2a-methyl-11fi,17u-dihydroxy- 21-iodo-4,6-pregnadiene-3,20-dione (XXVI) instead of 60: fiuoromethyl 11,19,170 dihydroxy 21 iodo 4- pregnene-3,20-dione and fiu-fluoromethyl 2oz methyl- 11,8,17a dihydrexy 7 21 iodo 4 pregnene 3,20- dione (XXVI).

The corresponding 9u-fluoro and 9a-chloro analogues of the compounds prepared in Example 51 are similarly produced.

EXAMPLE 52 6-fluorom ethyl-1 15,1 7c .-dihydrxy-21Jada-1,4,6- pregizatriene-3,20-dione (XXVI) EXAMPLE 53 One gram of 6u-fluoromethyl-l1fi,17a-dihydroxy-21- iodo-4-pregnene-3,20-dione (XXVI) was dissolved in 150 ml. of boiling acetronitrile. After cooling to' about 40 C., the solution was protected from light and 1.0 ml. of a 50% aqueous solution of silver fluoride was added with stirring. Stirring was continuedfor 1 hour at about 46 C., then an additional equal portion of silver fluoride solution was added. After another hour of stirring a third portion of the same quantity of aqueous silver fluo ride solution was added. Heating and stirring was then continued for a period of 2 hours, The brown mixture was then filtered through a bed of diatomaceous earth (Celite) and the filtrate evaporated at reduced pressure at a bath temperature of 50 C. The brown residue was thoroughly extracted with two portions of warm methylene chloride,'the combined extracts washed with Water and dried over anhydrous sodium sulfate. The dried solution was concentrated to a small volume and then chromatographed over a column of magnesium silicate (Florisil). The column was eluted with hexanes containing increasing proportions of acetone to give 60:- fiuoromethyl 115,17 dihydroxy 21 fluoro 4- pregnene-3,2 O-dione (XXIII).

In the same manner as given in Example 53, but substituting 6a fluorornethyl 115,17r dihydroxy 9ozfiuoro-Zl-iodo-4-pregnene-3,20-dione (XXVI) as starting compound, the corresponding fia-fluoromethyl-llfijhis thus produced. The corresponding 9u-chl0ro cornpounds are similarly prepared.

Following the procedureof Example 53, but substituting asstarting compounds 6a-fluOrOmethyl-Za-methyl- 115,17a dihydroxy 21 iodo- 4 pregnene 3,20- dione, 6o: iluoromethyl 16a methyl 11,8,1712 dihydroxy 21 iodo 4 pregnene 3,20 dione, 6ozfluoromethyl 165 methyl 115,170: dihydroxy 21- iodo-4-pregnene-3,ZO-dione and their corresponding 90:.- fluoro and their corresponding 904-11101'0 and 9a-chloro analogues (XXVI), there are thus produced, respectively, 6a fiuoromethyl 2a methyl 1113,1751 dihydroxy- 21 fiuoro 4 pregnene 3,20 dione, 6oz fiuorornethyl- 16oz methyl 11,6,17cc dihydroxy 21 tluoro 4 pregnene 3,20 dione, 6oz fiuoromethyl 165 methyl- 11,8,170L- dihydroxy 21;- fiuoro 4 pregnene 3,20- dione and their corresponding 9a-fiuoro and 9u-chloro analogues (XXIII).

EXAMPLE 54 Following the procedure of Example 53, but substituting as starting compounds the corresponding 1,4-pregnadienes for 4-pregnenes, there are thus produced the respective -21 -fiuoro 11,4 -pregnadienes, e.g., 6u-fluoromethyl-11fl,17a-dihydroxy-2l fiuoro 1,4 pregnadiene- 3,20-dione 6a fiuoromethyl 2 methyl 11 6,1711 dihydroxy-21-fiuoro-1,4-pregnadiene 3,20 dione and 6afluorornethyl 11,8,17oc dihydroxy 9u,2l difluoro- 1,4-pregnadiene-3,20-dione (XXIII) instead of 6a-fiuoromethyl 11,8,17a dihydroxy 21 fiuoro 4 pregnene 3,20 dione, 6a fluoromethyl 20c methyl- 11B,l7a dihydroxy 21 fluoro 4 pregnene 3,20- dione and 6a-fiuoromethyl-11,8,17a-dihydroXy-9a,2l-difluoro-4pregnene-3,2G-dione (XXIII).

EXAMPLE 55 Following the procedure of Example 53, but substinadienes for 4-pregnenes, there are thus produced the respective 21-f1uor0-4,6-pregnadienes, e.g., G-fluorornethyl 11,3,17u dihydroxy 21 fiuoro 4,6 pregnadiene 3,20 dione, 6 fluoron1ethyl 2m methyl 115,171!- dihydroxy-Qbfluoro 4,6 pregnadiene-3,20-dione and 6 fiuoromethyl 11fl,17oc dihydroxy :,21 difluoro- 4,6-pregnadicne-3,20-dione, instead or" 6wfluoromethyl- 2a methyl- 11fi,l7ot dihydroxy 21 fiuoro 4 pregnene-3,20-dione and 6tx-fluoromethyl-1lfl,l7ot-dihydroxy- 9a,21-difluoro-4-pregnene-3,20-dione (XXIII).

EXAMPLE 5 6 o-fluoromethyl-l 1,6,1 7adihydroxy-21-fluor0- 1,4,6-preglnatrierte-3,20-di0ne (XXIII) Following the procedure of Example 53, but substituting as starting compounds the corresponding 1,4,6-pregnatrienes for 4-pregnenes, there are thus produced the respective 2l-fiuorod,4,6-pregnatrienes, e.g., 6 fluoromethyl 116,170; dihydroxy 21 fluoro 1,4,6 pregnatriene 3,20 dione, 6 fluorornethyl 2 methyl 7 Ilfl,17uz L dihydroxy 21 fluoro 1,4,6 pregnatriene- EXAMPLE 61 A solution. was prepared containing 6a-fluoromethyi- 1153,17 dihydroxyu- 21 fluoro 4 pregnene-3-,20-dione (XXIII), chromic acid, glacial acetic acid and a small quantity of water. This mixture was stirred and then maintained for about 8 hours at; room temperature. Thereafter the 'mixturewas poured into ice water, neutralized by the. addition of dilute sodium hydroxide and the thus obtained precipitate collected on a 'filter and recrystallized three times from a mixtureiof' ethyl acetate and Skellysolve B 'hexanes to give 6a-fiuorom'ethyl-17a hydroxy-2 1-fiuoro-4-pregnene3,1 1,2 -trione (XXV) In the same manner as in Example 61,but substituting 6a -'fluoromethyl -'11,8,17ct dihydroxy 90:,21 difluoro- 4-pregnene-3,20-dione (XXEI) as star-ting compounds, the corresponding 6cc-11I1Q1OII161113Y1-17oc-hydrOXY-9a,21-d1- fluoro-4-pregnene-3,11,20-trione (XXV) is thus produced. The corresponding 9o-chloro-compound is similarly preared.

p In the same manner as in Example 61, butsub'stituting as starting compounds 6e-fluoromethyl-2a-methyh. 1 15,170; dihydroxy-Zl-fluoro-4-pregnene-3,ZO-dione, 6a-

3,11,20-trione, 6a fiuoromethyl 16,8 methyl 17oz hydroxy-Z1-fluoro-4-pregnene-3,11,20-t1ione and their corresponding 9a-fluoro and 9a-chloro analogues (XXV).

- EXAMPLE 62 6 a-fluOromethyf-J 7a-hydr0xy-21{Moro-1,4-pregnadiene- 3,1],20-tri0ne (XXV) Following the procedure of Example 61, but substituting as starting compounds, the corresponding 1,4-pregnadienes for 4-pregnenes, there are thus produced the respective 21-fluoro-1,4-pregnadienes, e.g., 6a-fluoromethyl- 17m hydroxy 21 fluoro 1,4 pregnadiene 3,11,20- trione, 6oz fluoromethyi-Z-methyl-17u-hydroxy-21-fiuoro- 1,4-pregnadiene-3,11,20-trione and 6a-fluoromethyl-17ahydroxy-9a,21-difluoro 1,4 pregnadiene 3,11,2Gtrione (XXV) instead of 6a-fluoromethyl-17a-hydroxy=2 1-fluoro-4-pregnene-3,11,20-trione, 6u-fluoromethyl-2a-methyl- 17a -hydroxy-21-fluoro-4-pregnene-3,11,20 trione and 6afluoromethyl 17a hydroxy 9a,21 difiuoro 4 pregnene-3,11,20-trione (XXV).

EXAMPLE 63 6 -fluorometlzyl-1 7cz-hydroxy-21-fluoro-4,6pregnadiene- 3,11,20-trione (XXV) Following the procedure of Example 61, but substitut- 38 EXAMPLE 64 roxy-;21 4 fiuoro 4 pregnene 3,11,20 trione, 6oziluorom'ethyl 2c: methyl 17oz hydroxy 21 efiuoro 4- pregnene-3,11,20-trione and 6o-fluoromethyl-'17 hydroxy 9a.,21-difluoro-4-pregnene-3,11,20-trione (XXV).

EXAMELE 65 150 mg. of 6a-fluoromethyl-11,8,17a-dihydroxy 21-iodo- 4-pregnenee3,20-dione (XXVI) was slurried with 5 ml.

" of acetic acid and stirred for a period of about minutes. Then an aqueous solution of 250 mg. of sodium thiosulfate pentahydrate was added causingthe' iodine color to disappear. Additional water was added and the mixture extracted with three portions of methylene chloride. The methylene chloride extraots'were combined,

' washed with Water and cold sodium bicarbonate solution ing as starting. compounds, the corresponding 4,6-pregmethyl-17a-hydroxy-21-fluoro-4-pregnene-3,11,20 trione and a fluoromethyl-17a-hydroxy-9a,21-difluoro-4preg nene-3,11,20-trione (XXV).

' column of magnesium silicate (Fiorisii).

until all the acetic acid was neutralized. After drying over anhydrous sodium sulfate, the solution was concentrated to a small volume and chromatographed over a The column was developed with hexanes containing increasing proportions of acetone, to give substantially pure 604-1111010- niethyl 1113,170; dihydroxy 4 pregnene 3,20 dione (XXVH). i

Following the procedure of Example 65, Ga-i'luoromethyl 1 18,17oc dihydroxy 9a fiuoro -21 iodo 4- pregnene-3,20-dione' (XXVI) is converted to 6oa-fluoromethyl 11,6,17a dihydroxy c fluo'ro 4 pregnene- 3,20-dione (XXVH). The corresponding 9a-chloro compound is simiiarly prepared. a I t Following the procedure of Example 65, but substitutas starting compounds, 61 fluoromethyl-2u-methyi-11e, 17 a-dihydroxy-Z 1-iodo-4-pregnene-3,ZO-dione, 62x fluoromethyl 16p? methyl-11,8,l7a-dihydr oxy-4-pregnene-3,29- dione, 6a-fiuoromethyl-16 Smethy1 l lfl,17a-dihydr0Xy-4 pregnene-3,20-dione and their corresponding 9a-fiuoro and 9a-chloro analogues (XXVl), there are thus produced, respectively, 6a-fiuoromethyl-2a-methyl-11fi,17x-dihydroxy- 4-pregnene-3,2{)-dione, 6a -i,fluoromethyl-16a-methyl-l1/3, 7a-dihydroxy-4-pregnene 3,20 dione, 60c fiuoromethyl- 16,8 methyl 115,170 dihydroxy 4 pregnene 3,20- dione and their corresponding 9u-fill0f0 and 9a-chloro analogues (XXVH).

EXAMPLE: 66

i 6a-flu0r0methyl-11,8,17a-dikyrlroxy-L4-pregnadiene-3,20di0ne (XXVII) Following the procedure of Example 65, but substituting as starting compounds, the corresponding 1,4-preg'nathemes for 4-pregnenes, there are thus produced the redrox -9cc-fiuoro-4-pregnene-3,20-dione (XXVII). g

EXAMPLE 67 6-flu0rontethyl-115J 7 a-dz'hydr 0xy-4,6-pregna dier ze-iZO-dione (XXVII) Following the procedure of Example 65, but substituting as starting compounds, the corresponding 4,6-pregnadienes for 4-pregnenes, there are thus produced the respective, 2l-methyl-1,4-pregnadiehes, e.g., 6-fiuoromethyl- 115,17ot-dihydroxy-4,6-pregnadiene 3,20-dione,-6-fluoro- '10 j j fluoro-ifi-pregnadiene-3,20-dione (XXVII) instead of 6w- 7 fluOrOrnethyl l1B,l7a-dihydroxy-4-pregnene 3,20 dione,

S -fluQIo A-Pregnene -B,ZO-diohe (XXVII),

v, 7 'EXAMPLE 68 6-fluorom ethyl-1 1l3,17a-'dihydi'0xy-1 ,4,6-pregnatrz' en-iZQ-dione (XXV 11) Folloiiving the procedure of Example 65, but substituting as starting compounds,,the corresponding 1,4,6-pregnatrienes for 4-pregnenes, there are thus produced the respective l 2l methyl-1,4,6 pregnatrienes, e.g.,; 6-fluoromethyl 'l 15,17ix-dihydroxy-L4,6-pregnatriene-3,20, -'dione,

droXy-9a-fluoro-1,4,6-pregnatriene-3,20'- dione (XXVII) instead of 6a-fiuorornethyl-l1B-17u-dihydroxy-4-pregnene 3,20 dione, 6 m fiuQromethyI-Za-methyI-I1/8,17a-dihy droxy-4 p'regnene-3,ZO-dione and 6ct-fiuoromethyl-11fi,17a 'dihydroXy-9..-.fiuoro-fl-pregnene-l ,ZO-dione (XXVHI) Z r E AMPLE 69 v V 6 u-fluoromethyl-l 7a-hydrdxy-4-prgneneQ 3,11,20-trz'0ne (XXVIII) A mixture was prepared containing 1.0 g. of fim-iiuoromethyl-115,170: dihydroxy 4 pregnene 3,20 "dione (XXVH),L350 mg; of chrornic anhydride, ml; ofgla'cial acetic acid and a small'arnount of water; This mixture was stirred and then maintained for about 8 hours at room temperature. Thereafter the mixture Was'poured into ice 7 Water, neutralized by .the addition of -dilute sodium hydroxidel and the thus-obtainedprecipitate collected on a filter and dried to give 6ct-fluonomethyl 17a-hydroxy-4- pregnene-3,11,20-trione (XXVHDV 7 Following the procedureyof Example 69,- oer-fluorornethyl-l15,17u-dihydroXy-9a-fluoro 4 preg'nene 3,20- dione (XXVII) was oxidized to 6a -fluoromethyl-l7a-hydroxy-9a-fiuoro-4-pregnene -V 3,1 1,20. trione' ()QfiVIII).

The corresponding 9a-chloro compound is similarly produced. l

,In the same manner as starting compounds 66t fluoromethyl-2a-methyl-1118, 17a-dihydroxye4-pregnene-3,2O dione, 6a -;fluoromethyl- 16a-n1ethyl-11,8,17a-dihydroxy-4-pregnene 3,201 dione,

-6a-fluoromethyl-16B-methyl l15,17a-dihydroxy 4pregnen e-3,20-dione and their corresponding 9a-fluoro and 90achloro analogues (XXVII), there are thus produced,'re-

' spectively,16a-fiuorornethyl Za-methyL- I7a-hydroxy-4- pregnene-3,11,20-trione, 6a-fluoromethyl-l6a-rnethyl 17aa-fiuoromethyhlwi' l methyl 17a-hydroxy-4-pregnene-3,11,2(1-trione and 'their corresponding 9a-fiuoro and 7 9oz chloro analogues hydroxy-4-pregnene-3 ,1 1,20-trione,

Following the procedure of Example 6 9, but substituting as starting compounds, the corresponding .llfi-hydroxy- 1,4;pregnadienes for 1lfi-hydroxy-mpregnenes, there are thus produced the respective '11-ket0-1,4 pregnadienes, e.g.,

V V V '6ot-fluoromethyl-17a-hydroXy-L4 {pregnadie'ne 3,11,20-

V fiuoro ifl-pregnene-ll1,20-trione (XXVHI). I

trione, 6a-fluoromethy1l-2-methyl-17a-hydroxy-l,4-pregnadiene-3,11,20-tr ione and u-fluoromethyl-17u-hydroxy-9u- I fluoro-1,4-pregi1adiene-3,11,20-trione (XXVHI) instead of 6a-fiuorornethyl-17u-hydroxy-4-pregnene-3,11,20 trione,

as s r i ac pm ndr vthe r e p n lIfi-Wdwfl- 4,6-pregnadi enesiforn11B-hydroXyA pregnenes;there are 1" 15 e g., 6-fluoron1ethyl-17a hydroXy-4,6-pregnadiene-3;11,20

mixture was poured with vigorous stirring into Water, The precipitated solid was separated by filtration, dried and" the 6:;- fluoromethyl-l1p,17a-dihydroxy-4-pregnene-3,20-

as in Example 69, but substituting anhydride), 'propionic, butyrici isobutyric, 'v'aleric, iso V colored crystals;

thus produced therespective 11-keto 4,6 pregnadienes,

trione, 6-fiuoromethyl-2ez-rnethyl-17a-hydroxy-4,6:pregna diene-3,11,20-trione and 6 fiuoron1'ethyl-17a hydroxy-9a?. fluoro-4,6-pregnadiene-3,11 ,20 trione ()QQVDI) instead of 6oc fiuoromethyl-j17 ii-jhydroxy-4-pregnenei 311,20 trione', 6a-fiuoromethyl-2oz-methyl's- 17a" hydroxy-A pregnen e EXAMPLE V V 3,11,2011'207155 (XXVIH) Following the procedure of Example 69, but substituting as starting compounds, the corresponding llfi-hyd'roxy 1,4,6-pregnatrienes for llfi -hydroxy -pregnenes, there are thus producedthe respective 1 1-'keto-1,4,6-pregnatrienes, e.g., 6-fluorornethy1-17u-hydroxy1,4,6-pregnatriene 1 1,4,6-pregnatriene-3,11,20-trione and 6-fluoromethyl-l7 a hydroxy 9m fiuoro 1,4,6-pregn'atriene- 3A1,20-trione (XXVHD instead of 6 x-fiuoron1ethy-lfiqrhydroxyA-preg j nene-3,11,20 -ltrione, 6a-fluor'omethy1-2a-ntethyl-l7cz-hy{- droXy-4-pregnene-3,'11,20-trione and Ga-fiuOIOmethyI-I'Zahydroxy-Sa-fluorol-pregnenefi,lLZO-trione (XXVIII). 7

' u ExAMrLE 73 6a-fluoromethyl-115,1i -dihydroxy 4-pregriena 3,20-dione 17-acetate' (XX[X) i ,A solution of 2.0 g; of 6a'-fiuoromethy1-11 3,17a-di hydroxy-4-pregnene-3,ZO-dione (XXVII), 5 ml. of distilled acetic anhydride, 0.5 g. ofjp-toluene sulf onicacid and '5' ml. .of acetic acidwas stirred for about minutes; The

dione' l7 a'cetate (XXIX) thus obtained was chro'matoi graphed over Florisil synthetic magnesium silicatefwith increasing proportions of acetone in Skellysolve B hexane] :ethyl acetate to give 'llig'ht and was recrystallized from 7 Substituting another lower-hydrocarbon carboxylic acid anhydride for the acetic anhydride is productive of other 6c -'fiuoromethyl 115,176: dihydroxy-4 pregnene-3,20 dione 17-acylates (XXIX) wherein the :acyl radical of;

the acyla te group is'the 'acyl radicallof, for eirarnpleQa lower-aliphatic acid, e.g., formic (formic acid plus :acetic valeric, trimethylacetic," 2-methylbutyric, 3-ethylbutyric, heXanoic, diethylacetic, triethylacetic heptanoic, 'octanoic, a ethylisovaleric, a cyclic acid, e.g.,, cyclopropylideneacetic, a cycloaliphatic acid, elg.,'cycloperitylformic c'yclo} pentylacetic, ,8 -cyclopentylpropionic, cyclohexylformic,

cyclohexylacetic, ,S-cyclohexylpropioniqan aryl or alkarylf '7 acid, e.g., ben zoi'c, methylhen'zoic, dimethylbe'nzoigethyl-V benz'oic, trimethylbenzoic, m naphthoic, 3 methyl:ci naphthere, an aralkyl acid, e.g., phenylacetic, phenylpropionic,

diphenylacetic, and triphenylaceticacid; m

" in the same. manner as in Example 13, buil sllbSiiilltihgi 6a-fiuorornethyl-1 15, 1 Yrs-d1hydroxyfia-fiuoro-4-pregnenp J 

3. 6A - FLUOROMETHYL - 11B,16A,17A,21 - TETRAHYDROXY - 4PREGNENE-3,20-DIONE 16A, 17A-ACETONIDE REPRESENTED BY THE FORMULA: 